Novel tetrahydrocarbazole derivatives having improved biological action and improved solubility as ligands of G-protein coupled receptors (GPCPs)

ABSTRACT

The present invention provides novel tetrahydrocarbazole derivatives which have improved properties and which can be employed as inhibitors of GPCRs. This results in the possibility of using the novel compounds to treat pathological conditions whose severity depends on the pathobiochemical effect of GPCRs. The compounds of the invention act in particular via an antagonistic inhibition of the LHRH receptor. The invention further provides medicaments which comprise one or more of the novel compounds as active ingredient. The medicaments are suitable in particular to be employed in an oral dosage form for a mammal, in particular a human.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/172,142, nowallowed, which claims the benefit of priority of Provisional ApplicationNo. 60/587,969, filed on Jul. 14, 2004, Provisional Application No.60/683,178, filed on May 20, 2005, and German Application No. 10 2004033 902.3, filed on Jul. 14, 2004, each of which is incorporated in itsentirety herein by reference thereto.

FIELD OF THE INVENTION

The present invention relates to novel tetrahydrocarbazole derivativeshaving improved biological action, improved oral bioavailability andimproved metabolic stability as ligands of G-protein coupled receptors(GPCRs), in particular as ligands of the receptor for luteinizinghormone releasing hormone (LHRH receptor), to the preparation thereof,and to the use thereof in pharmaceutical compositions for the treatmentof pathological conditions mediated by G-protein coupled receptors in amammal and in particular in a human.

BACKGROUND OF THE INVENTION

The contents of all the publications cited in this application, orcomparable sources which are quoted, in order to explain the backgroundof the invention are incorporated in the present application for thepurpose of the disclosure.

G-protein coupled receptors represent a superfamily of cellmembrane-associated receptors which play an important part in numerousbiochemical and pathobiochemical processes in mammals and especially inhumans. AU GPCRs consist of seven hydrophobic, transmembranealpha-helical domains which are connected together by threeintracellular and three extracellular loops and have an extracellularamino terminus and an intracellular carboxy terminus. One or moreheterotrimeric G proteins are involved in their cellular signaltransduction. Diverse physiological stimuli such as photosensitivity,taste and odor, but also fundamental processes such as metabolism,reproduction and development are mediated and controlled by them. GPCRsexist for erogenous and endogenous ligands. Peptide hormones, biogenicamines, amino acids, nucleotides, lipids, Ca²⁺, but also photons, haveinter alia been identified as ligands; moreover one ligand may activatedifferent receptors.

According to a recent investigation, 367 sequences have been identifiedin the human genome for G-protein coupled receptors (GPCRs) withendogenous ligands, D. K. Vassilatis et al., PNAS 100(8), 4903-4908(2003). Of these, 284 belong to class A, 50 to class B, 17 to class Cand 11 to class F/S. Examples belonging to class A are the bombesin, thedopamine and the LHRH receptors, and to class B are the VIP and thecalcitonin receptors. The natural ligands for numerous GPCRs are as yetunknown.

Owing to their function, GPCRs are suitable as targets for medicamentsfor the therapy and prevention of a large number of pathologicalconditions. It is speculated that about 50% of currently known targetsfor active ingredients are GPCRs [Y. Fang et al., DDT 8(16), 755-761(2003)]. Thus, GPCRs play an important part in pathological processessuch as, for example, pain (opioid receptor), asthma (β₂-adrenoceptor),migraine (serotonin 5HT1B/1D receptor), cancer (LHRH receptor),cardiovascular disorders (angiotensin receptor), metabolic disorders(GHS receptor) or depression (serotonin 5-HT_(1a) receptor), K. L.Pierce et al., Nat. Rev. Mol. Cell Biol. 3, 639650 (2002).

General information about GPCRs is to be found underhttp://www.gpcr.org.

The present invention describes novel ligands with improved propertiesfor GPCRs in general, the compounds provided by the invention acting inparticular as antagonists of the LHRH receptor.

The natural ligand of this receptor, the peptide hormone LHRH, issynthesized in cells of the hypothalamus and released in pulsatilefashion from the hypothalamic neurons into the capillary plexus of theementia mediana. In the anterior lobe of the pituitary, LHRH binds tothe LHRH receptors of the gonadotropic cells and stimulates certaintrimeric G-proteins, which initiate a branched signal transductioncascade. The initial event is activation of phospholipase C, A2 and/orD. This leads to an increased provision of the second messengersdiacylglycerol and IP₃, followed by Ca²⁺ mobilization from intracellularpools, and activation of various subordinate protein kinases. Finally,there is stimulation of the production and temporally defined pulsatilerelease of the gonadotropins FSH and LH. The two hormones aretransported via the circulation to the target organs the testes andovaries respectively. There they stimulate the production and release ofthe appropriate sex hormones. In the opposite direction there is acomplex feedback mechanism by which the concentration of the sexhormones formed in turn regulates the release of LH and FSH.

In the male organism, LH binds to membrane receptors of the Leydig cellsand stimulates testosterone biosynthesis. FSH acts via specificreceptors on the Sertoli cells and assists the production ofspermatozoa. In the female organism, LH binds to the LH receptors of thetheca cells and activates the formation of androgen-synthesizingenzymes. FSH stimulates proliferation of granulosa cells of certainfollicle stages via the FSH receptors thereof. The androgens which areformed are converted in the adjacent granulosa cells to the estrogensestrone and estradiol.

A number of disorders distinguished by benign or malignant tissueproliferations depend on stimulation by sex hormones such astestosterone or estradiol. Typical disorders of this type are prostatecancer and benign prostate hyperplasia (BPH) in men, and endometriosis,uterine fibroids or uterine myomas, pubertas praecox, hirsutism andpolycystic ovary syndrome, and breast cancer, uterine cancer,endometrial cancer, cervical cancer and ovarian cancer in women.

Since its discovery in 1971 by Schally et al. Science 173, 1036-1038(1971), more than 3000 synthetic analogues of natural LHRH have beensynthesized and tested. Peptide agonists such as triptorelin andleuprolide have been established for many years successfully in thetherapy of gynecological disorders and cancers. However, thedisadvantage of agonists is generally that they stimulate LHRH receptorsin the initial phase of use and thus lead to side effects via an initialincrease in the sex hormone levels. Only after downregulation of theLHRH receptor as a result of this overstimulation can the superagonistsdisplay their effect. This leads to a complete reduction in the sexhormone levels and thus to pharmacological castration with all the signsand symptoms. This disadvantage is associated with the impossibility oftargeted adjustment of the level of sex hormones via the dosage. Thus,therapy of diseases which do not require a total reduction of the sexhormone levels to the castration level, such as, for example, benigntissue proliferations, with an agonist is not optimal for the patient.

This has led to the development of peptide LHRH receptor antagonists, ofwhich, for example, cetrorelix (Cetrotide®) has been successfullyintroduced for controlled ovarian stimulation in the context of thetreatment of female infertility. The antagonists inhibit the LHRHreceptor immediately and dose-dependently, and thus lead to an immediatereduction in the plasma levels of testosterone or estradiol andprogesterone. The peptide antagonists are, however, somewhat less potentthan the agonists, and thus higher doses must be given.

A review of the clinical applications and the potential of LHRH agonistsand antagonists is given by R. P. Millar et al. in British Med. Bull.56, 761-772 (2000) and R. E. Felberbaum et al., Mol. Cell Endocrinology166, 9-14 (2000) and F. Haviv et al. in Integration of PharmaceuticalDiscovery and Development Case Studies, Chapter 7, ed. Borchardt et al.,Plenum Press, New York (1998). Besides the treatment of malignant andbenign neoplastic diseases, further possible applications are controlledovarian stimulation in the context of in vitro fertilization, fertilitycontrol (contraception), and protection from unwanted side effects ofradio- or chemotherapy, the treatment of HIV infections (AIDS) and ofneurological or neurodegenerative disorders such as Alzheimer's disease.Specific LHRH receptors have not only been found on pituitary cells, butalso on cells in various tumors, e.g. of the breast and ovaries. Thesereceptors might mediate a direct antiproliferative effect of LHRHreceptor antagonists on the tumor.

The peptide LHRH receptor agonists and antagonists are mostlydecapeptides whose bioavailability is inadequate for oraladministration. They are typically given as solutions for injection oras depot formulation, subcutaneously or intramuscularly. Thisapplication is associated with inconveniences for the patient, and thecompliance suffers. In addition, synthesis of the decapeptides iscomplicated and costly.

It is therefore sensible to look for non-peptide LHRH receptorantagonists which, besides high activity, have an improved metabolicstability and can be administered orally.

PRIOR ART

Compared with peptide LHRH receptor agonists and antagonists, as yet nonon-peptide compound is approved and in clinical use for any of thepossible indications. The current state of development in the area ofLHRH receptor agonists and antagonists is described in the reviews byY.-F. Zhu et al., Expert Opin. Therap. Patents 14(2), 187-199 (2004),Y.-F. Zhu et al., Ann. Rep. Med. Chem. (39), 99-110 (2004), F. C. Tucciet al., Curr. Opin. Drug Discovery & Development 7(6), 832-847 (2004),R. E. Armer, Curr. Med. Chem. 11, 3017-3028 (2004) and M. V. Chengalvalaet al., Curr. Med. Chem. —Anti-Cancer Agents, 3, 399-410 (2003). Theformer publication contains a comprehensive list of the published patentspecifications describing the synthesis and use of low molecular weightLHRH receptor antagonists.

Among the first examples of non-peptide LHRH receptor antagonists is the4-oxothieno[2,3-b]pyridine structure, which was described by N. Cho etal. in J. Med. Chem. 41, 4190-4195 (1998). Although these compounds,such as, for example, T-98475, have a high receptor affinity; theirsolubility in water is very poor and their bioavailability is low. Basedon this lead structure, numerous further developments have been carriedout, examples which may be mentioned being the publications of theinternational applications WO 95/28405, WO 96/24597, WO 97/14697 and WO97/41126. The synthesis of thieno[2,3-d]pyrimidine-2,4-diones as orallyavailable LHRH receptor antagonists is described by S. Sasaki et al., inJ. Med. Chem. 46, 113-124 (2003).

Novel 1-arylmethyl-5-aryl-6-methyluracils are described by Z Guo et al.,in J. Med. Chem. 47, 1259-1271 (2004). The preparation ofN-[(hetero)arylmethyl]benzene-sulfonamides as potent non-peptide LHRHreceptor antagonists is disclosed in WO 03/078398. The patentapplication WO 02/11732 describes tricyclic pyrrolidines as LHRHreceptor antagonists. Substituted pyridin-4-ones as LHRH receptorantagonists are disclosed in WO 03/13528 and substituted1,3,5-triazine-2,4,6-triones in WO 03/11839.

The syntheses and biological activities of erythromycin A derivativeshaving LHRH receptor antagonistic activity is described by J. T.Randolph et al., in J. Med. Chem. 47(5), 1085-1097 (2004). Selectedderivatives show an oral activity on the LH level in the castrated ratsmodel.

Quinoline derivatives as non-peptide LHRH antagonists are disclosed forexample in WO 97/14682. Substituted 2-arylindoles are described interalia in WO 97/21435, WO 97/21703, WO 98/55116, WO 98/55470, WO 98/55479,WO 99/21553, WO 00/04013 as LHRH receptor antagonists. Correspondinglysubstituted aza-2-arylindoles are claimed inter alia in WO 99/51231, WO99/51596, WO 00/53178 and WO 00/53602 as LHRH receptor antagonists.Advantageous biological or biophysical data for these compounds are notdisclosed.

The patent EP 0 679 642 B1 describes fused heterocyclic compounds asLHRH receptor antagonists. The basic tetrahydrocarbazole structure is,however, not the subject matter of the invention described therein.

1,2,3,4-Tetrahydrocarbazolecarboxylic acids are described in the patentEP 0 239 306 B1 as prostaglandin antagonists. An LHRH receptorantagonistic effect is neither described nor obvious. U.S. Pat. No.3,970,757 discloses tetrahydrocarbazole derivatives as gastricanti-secretory agents. However, an LHRH receptor antagonistic effect ofthis type of structure is neither described nor obvious. EP 603 432 B1and U.S. Pat. No. 5,708,187 describe tetrahydrocarbazole derivatives as5HT1 agonists inter alia for the treatment of migraine.

However, an LHRH receptor antagonistic effect is neither described norobvious. WO 2005/033099 A2 describes tetrahydrocarbazole derivatives asdipeptidyl peptidase IV inhibitors. However, an LHRH receptorantagonistic effect is neither described nor obvious. There is noreference to an LHRH receptor antagonistic effect, and the disclosedstructures differ from the compounds of the present invention. D. J.Davies et al. describe in J. Med. Chem. 41, 451-467 (1998)tetrahydrocarbazole derivatives having a melatonin agonistic orantagonistic effect. However, an LHRH receptor antagonistic effect isneither described nor obvious. Tetrahydrocarbazole derivatives aredescribed by S. J. Shuttleworth et al. in Bioorg. Med. Chem. Lett. 14,3037-3042 (2004) as partial agonists of the neuromedin B receptor.However, an LHRH receptor antagonistic effect is neither described norobvious. R. Millet et al. describe in Letters in Peptide Science 6,221-233 (1999) tetrahydrocarbazole derivatives as NK₁/NK₂ ligands. Thedisclosed structures differ from the compounds of the present invention.Moreover, an LHRH receptor antagonistic effect is neither described norobvious. Solid-phase synthesis of 3-amino-3′-carboxytetrahydrocarbazolesis in Koppitz et al., THL 46(6), 911-914 (2005). An LHRH receptorantagonistic effect is neither described nor obvious.

Tetrahydrocarbazole derivatives as peptidomimetic LHRH receptorantagonists having good receptor affinity are disclosed for example inWO 03/051837 (DE 101 64 564 A1).

The physicochemical and metabolic properties of these compounds do not,however, make them suitable in an optimal manner for an oral dosageform.

A number of publications provide an overview of the state of developmentof neurokinin antagonists. G. Giardina et al., IDrugs 6(8), 758-772(2003), provide an overview of the current patent literature. V. Leroyet al., Expert Opinion on Investigational Drugs 9(4), 735-746 (2000),and C. Swain et al., Annual Reports in Medicinal Chemistry 34, 51-60(1999) describe the state of development relating to neurokinin receptorantagonists, while, for example, R. M. Navari et al., CancerInvestigation 22(4) 569-576 (2004) describes the results of clinicalstudies in which NK1 receptor antagonists were employed to controlchemotherapy-induced emesis. R. G. Hill et al. describe in Pain, 523-530(2003) neurokinin receptor antagonists as potential analgesics, while A.von Sprecher et al. in IDrugs 1(1), 73-91 (1998), describe neurokininreceptor antagonists as potential active ingredients for the therapy ofinflammations and rheumatoid arthritis. R. Millet et al. describe inLetters in Peptide Science 6, 221-233 (1999) tetrahydrocarbazolederivatives as NK₁/NK₂ ligands. The disclosed structures differ from thecompounds of the present invention.

OBJECT OF THE INVENTION

The object of the present invention is to provide novel compound whichhave improved oral bioavailability and improved metabolic stability andwhich can be employed for the treatment of pathological conditionsmediated by GPCRs in mammals and in particular in humans. It ispreferably intended that the novel compounds display their biologicalaction via an antagonistic inhibition of the LHRH receptor. The novelcompound we intended to be suitable for achieving the desired effect ina dosage which is acceptable for use and dose-dependently in an oralformulation. For this it is necessary to be able to use the novelcompounds as pharmacologically active ingredients in a medicament inmammals or humans.

The inventive object is achieved in a surprising manner through theprovision of the novel, improved tetrahydrocarbazole derivatives of thegeneral formula (I) below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-7 show the measured competition plots of the LHRHreceptor-ligand binding assays with [¹²⁵I][D-Trp6]-LH-RH and theselected substances (7, 48, 66, 67, 68, 75 and 76).

FIGS. 8-11 show competition plots measured in the NK1 and NK2receptor-ligand binding assays with [Sar⁹, Met(O₂)¹¹]-SP for NK1 and[Nle¹⁰]-NKA(4-10) for NK2, and the selected substances (68 and 76).

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention relates to noveltetrahydrocarbazole compounds of the general formula (I):

in which:

-   X₁ is S or O,-   X₂ and X₃ are independently of one another O or geminally linked H₂,-   R1 and R2 are independently of one another selected from the group    consisting of —H, aryl, alkyl and arylalkyl radicals which are    optionally substituted in the alkyl and/or aryl group by tip to 3    substituents independently selected from the group consisting of    -Hal, —CN and —O-alkyl, where R1 and R2 are in particular each a    hydrogen atom,-   R3 is an alkyl, arylalkyl or heteroarylalkyl radical, which are    optionally substituted by tip to 3 substituents independently    selected from the group consisting of -Hal, —CN, —CO—O—R12,    —CO—NR12R12′, —OH, —O—R13, —O—CO—R13, —O—SO₂—OR12, —O—SO₂—R12,    —SO₂—OR12, —SO—R12, —O—PO(OR12)(OR12′), —O—PO(NR12R12′)₂,    —O—CO—O—R13, —O—CO—NR12R12′, —O—CS—NR12R12′, —S—R12, —NR12R12′,    —NH—CO—R13, —NH—SO₂—R12, —NH—CO—O—R13, —NH—CO—NHR12, —NH—C(NH)—NH₂,-   R4, R5, R6 and R7 are selected independently of one another from the    group consisting of H, -Hal, —CN, —CONH₂, —COOH, —CF₃, —O-alkyl,    —OCF₃, —NO₂, and alkyl, arylalkyl and heteroarylalkyl radicals;-   R9 is a hydrogen atom, an alkyl, an aryl, a heteroaryl, an arylalkyl    or a heteroarylalkyl radical, preferably a hydrogen atom;-   R10 is a hydrogen atom, or the radical —R11, —CO—R11, —CO—OR11,    —CO—NHR11, —C(NH)—NHR11, —SO₂—R11, or —SO₂—NHR11;-   R11 is an alkyl, an aryl, a heteroaryl, an arylalkyl or a    heteroarylalkyl radical, which are optionally substituted by one or    more substituents independently selected from the group consisting    of -Hal, —CN, -alkyl, —CF₃, —OCF₃, —OH, —O-alkyl, and    —O—(CH₂CH₂—O)_(n)—CH₃;-   R8 is —C₁-C₆-alkyl-aryl or —C₁-C₆-alkyl-heteroaryl, where the aryl    or heteroaryl group is substituted by tip to three, i.e. by at least    one, two or three substituents, preferably by one substituent,    independently selected from the group consisting of    —O—(CH₂CH₂—O)_(n)—CH₃, —O—CO—R12, —O—CO—(CH₂CH₂—O)_(n)—CH₃,    —O—SO₂—OR12, —O—SO₂—R12, —O—PO(OR12)(OR12′), —O—PO(NR12R12′)₇,    —O—CO—OR13, —O—CO—NR12R12′, and —O—CS—NR12R12′, or,    -   where, however, at least        -   (i) X₁ is S, or        -   (ii) R10 is not H, and R11 is an arylalkyl or            heteroarylalkyl radical, which are substituted in the aryl            or heteroaryl group by one or more substituents, preferably            by one, two or three substituents, independently selected            from the group consisting of Hal, —CN, -alkyl, —CF₃, —OCF₃,            —OH, —O-alkyl, and —O—(CH₂CH₂—O)_(n)—CH₃.        -   R8 also assumes the meanings indicated for R3;-   R12 and R12′ are independently of one another H, or an alkyl,    arylalkyl, aryl, heteroarylalkyl, or heteroaryl radical, preferably    hydrogens.-   R13 is selected from an alkyl, arylalkyl, aryl, heteroarylalkyl, and    heteroaryl radical, or is the group —(CH₂CH₂—O)_(n)—CH₃, and-   n is an integer from 1 to 10, preferably 1 to 6.

The terms indicated for explanation of the compounds of the generalformula (I) always, unless indicated otherwise in the description or inthe claims, have the following meanings:

the term “substituted” means that the corresponding radical or group hasone or more substituents. Where a radical has a plurality ofsubstituents, and a selection of various substituents is specified, thesubstituents are selected independently of one another and need not beidentical. The term “unsubstituted” means that the corresponding grouphas no substituent. The term “optionally substituted” means that thecorresponding group is either unsubstituted or substituted by one ormore substituents. The term “substituted by up to 3 substituents” meansthat the corresponding radical or group is substituted either by one orby two or three substituents.

The term “halogen atom” or “halogen substituent” (Hal-) refers to one,where appropriate, a plurality of fluorine (F, fluoro), bromine (Br,bromo), chlorine (Cl, chloro), or iodine (I, iodo) atoms. Thedesignations “dihalogen”, “trihalogen” and “perhalogen” referrespectively to two, three and four substituents, where each substituentcan be selected independently from the group consisting of fluorine,chlorine, bromine and iodine. “Halogen” preferably means a fluorine orchlorine atom.

The term “alkyl” includes for the purposes of this invention acyclicsaturated or partially unsaturated hydrocarbons having C1-C12 carbonatoms, which may be straight-chain or branched. The term “alkyl”preferably stands for alkyl chains of 1 to 8, particularly preferably 1to 6, carbon atoms Examples of suitable alkyl radicals are methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, n-undecyl, n-dodecyl, propenyl, butenyl, pentenyl, hexenyl andoctadienyl. The term “alkyl” likewise stands for a saturated orpartially unsaturated cycloalkyl radical, preferably from the group ofcyclo(C3-C8)alkyl. Examples of suitable cycloalkyl radicals arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclohexenyl, cyclopentenyl, cyclooctadienyl and others. Inaddition, the term “alkyl” includes cycloalkylalkyl groups, withpreference for the cyclo(C3-C8)alkyl-(C1-C4)alkyl radical. Examplesthereof are cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl,cyclohexenylethyl. Thus, the term C₁-C₄-alkyl includes at least thefollowing groups: methyl, ethyl, n-propyl, isopropyl, propenyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl,cyclopropyl-methyl, and butenyl. Particularly preferred as C₁-C₄-alkylare isopropyl, sec-butyl, and cyclopropylmethyl.

Such alkyl radical may be unsubstituted or optionally also mono- orpolysubstituted, where the substituents may be identical or differentand be bonded in each or more than one desired and possible position ofthe alkyl. In the case of a mono- or poly-halogen-substituted alkylradical, substitution with fluorine and/or chlorine atoms is preferred.Examples of such radicals are fluoromethyl, trifluoromethyl andpentafluoroethyl.

“Aryl” refers to aromatic hydrocarbon systems having 3 to 14, preferably5 to 14, carbon atoms, which may also be fused to further saturated,(partially) unsaturated or aromatic ring systems. Examples of ‘aryl’ areinter alia phenyls, naphthyls and anthracenyls, but also indanyls,indenyls, or 1,2,3,4-tetrahydronaphthyls; phenyl is particularlypreferred for the purposes of the present invention. Such aryl radicalmay be unsubstituted or optionally also mono- or polysubstituted, wherethe substituents may be identical or different and be bonded in each ormore than one desired and possible position of the aryl.

“Heteroaryl” refers to a 5-, 6- or 7-membered cyclic aromatic radicalwhich comprises at least 1, where appropriate also 2, 3, 4 or 5,heteroatoms, preferably nitrogen, oxygen and/or sulfur, where theheteroatoms are identical or different. The number of N atoms ispreferably between 0 and 3, and that of the oxygen and sulfur atoms isbetween 0 and 1. The term “heteroaryl” also includes systems in whichthe heterocycle is part of a bi- or polycyclic system, it being possiblefor the linkage of the heteroaryl radical to the compounds of thegeneral formula (I) to take place via any desired and possible ringmember of the heteroaryl radical. Examples of “heteroaryl” includepyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,quinolinyl, and isoquinolinyl. Such heteroaryl radicals may beunsubstituted or optionally mono- or polysubstituted, where thesubstituents may be identical or different and be bonded in each or morethan one desired and possible position of the heteroaryl.

“Arylalkyl” or “heteroarylalkyl” refer to radicals in which the aryl orheteroaryl radical is linked via a C, Cg-alkyl group to the compound ofthe general formula (I), where the alkyl, aryl and heteroaryl groupshave the meanings defined above. Preferred “arylalkyl” groups arephenyl-C₁-C₄-alkyl radicals, preferably benzyl or phenylethyl radicals.

A “ring system” refers to a mono- or polycyclic system of 3 to 14,preferably 5 or 6 to 14 ring atoms which may be exclusively carbonatoms. However, the ring system may also comprise 1, 2, 3, 4, or 5heteroatoms, in particular nitrogen, oxygen and/or sulfur. The ringsystem may be saturated, mono- or polyunsaturated or entirely or partlyaromatic, and in the case of a ring system consisting of at least tworings the rings may be fused or spiro- or otherwise connected.

As mentioned above in connection with the general formula (I), thecompounds of the invention may, because they have at least one center ofasymmetry, exist in the form of their racemates, in the form of the pureenantiomers and/or diastereomers or in the form of mixtures of theseenantiomers and/or diastereomers The mixtures may have any desiredmixing ratio of the stereoisomers.

Preferred compounds of the general formula (I) are those which are inthe R configuration at the carbon atom substituted by —NH—CX₃— and—CX₃—NH—, i.e. have the following general formula (I-a):

Particularly preferred compounds of the general formula (I) are thosewhich are in the R configuration at the carbon atom substituted by—NH—CX₃— and —CX₂—NH—, in the S configuration at the carbon atomsubstituted by —CX₃—NH—, —R8 and —NR9R10, and likewise in the Sconfiguration at the carbon atom substituted by —NH—CX₂—, —R3 and—CX₁—NR1R2, i.e. have the naturally occurring S configuration of thecorresponding amino acids at these stereo centers. These compounds havethe following general formula (I-b):

Where possible, the compounds of the invention may be in the form of thetautomers.

Thus, for example, the compounds of the invention of the general formula(I) which have one or more centers of chirality and which occur asracemates or as diastereomer mixtures can be fractionated by methodsknown per se into their optical pure isomers, i.e. enantiomers ordiastereomers. The separation of the compounds of the invention or theirbuilding blocks (amino acids) can take place by column separation onchiral or nonchiral phases or by recrystallization from an optionallyoptically active solvent or with use of an optically active acid or baseor by derivatization with an optically active reagent such as, forexample, an optically active alcohol, and subsequent elimination of theradical.

The compounds of the invention of the general formulae (I, Ia and Ib)can, if they have a sufficiently basic group such as, for example, asecondary or tertiary amine, be converted with inorganic and organicacids into salts. The pharmaceutically acceptable salts of the compoundsof the invention of the general formulae (I, Ia and Ib) are preferablyformed with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonicacid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid,racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid,lactic acid, citric acid, taurocholic acid, glutamic acid or asparticacid. The salts which are formed are, inter alia, hydrochlorides,hydrobromides, sulfates, phosphates, methanesulfonates, tosylates,carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates,oxalates, malonates, maleates, succinates, tartrates, malates,embonates, mandelates, fumarates, lactates, citrates and glutamates. Thestoichiometry of the salts formed from the compounds of the inventionmay moreover be an integral or non-integral multiple of one.

The compounds of the invention of the general formulae (I, Ia and Ib)can, if they contain a sufficiently acidic group such as, for example,the carboxy, sulfonic acid, phosphoric acid or a phenolic group, beconverted with inorganic and organic bases into their physiologicallytolerated salts. Examples of suitable inorganic bases are sodiumhydroxide, potassium hydroxide, calcium hydroxide, and of organic basesare ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dibenzylethylenediamine and lysine. The stoichiometry of the saltsformed from the compounds of the invention can moreover be an integralor non-integral multiple of one.

It is likewise possible for the compounds of the invention of thegeneral formulae (I, Ia and Ib) to be in the form of their solvates and,in particular, hydrates which can be obtained for example bycrystallization from a solvent or from aqueous solution. It is moreoverpossible for one, two, three or any number of solvate or water moleculesto combine with the compounds of the invention to give solvates andhydrates.

It is known that chemical substances form solids which exist indifferent order states which are referred to as polymorphic forms ormodifications. The various modifications of a polymorphic substance maydiffer greatly in their physical properties. The compounds of theinvention of the general formulae (I, Ia and Ib) can exist in variouspolymorphic forms, and certain modifications may moreover be metastable.All these polymorphic forms of the compounds of the general formulae (I,Ia and Ib) are to be regarded as belonging to the invention.

It is likewise possible for the compounds of the invention of thegeneral formulae (I, Ia and Ib) to be in the form of any desiredprodrugs such as, for example, esters, carbonates or phosphates, inwhich cases the actually biologically active form is released onlythrough metabolism.

It is known that chemical substances are converted in the body intometabolites which may where appropriate likewise elicit the desiredbiological effect—in some circumstances even in more pronounced form.

It is known for thioamides (X₁═S) for example (Casarett & Doull's“Toxicology, the Basic Science of Poisons”, Chapter 6: Biotransformationof Xenobiotics, C. D. Klaassen Ed., McGraw-Hill 2001; D. M. Clayton,Biochem. Soc. Trans., 1978, 6(1), 94-96) that they can also bemetabolized to thioamide S-oxides. These substances can also be obtainedby synthesis from the corresponding thioamides by oxidation withhydrogen superoxide (H₂O₂) (J. R. Cashman et al., J. Org. Chem., 1982,47 (24), 4645-4650). Thus, compound 68 is oxidized for example to(R)-8-chloro-6-fluoro-3-((S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid ((S)-2-methyl-1-thiocarbamoylbutyl)amide S-oxide, and compound 76is oxidized to(R)-3-((S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino)-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid ((S)-2-methyl-1-thiocarbamoylbutyl)amide S-oxide.

Corresponding metabolites of the compounds of the general formulae (I,Ia and Ib), especially with X₁═—S′—O—, are to be regarded as belongingto the invention.

It may additionally be remarked at this point that the term “receptorligand” or “ligand” is intended to refer for the purposes of the presentinvention to every compound which binds in any way to a receptor (thereceptor in the present invention is a GPCR receptor, preferably an LHRHreceptor) and induces either activation, inhibition and/or anotherconceivable effect at this receptor. The term “ligand” thus includesagonists, antagonists, partial agonists/antagonists and other ligandswhich cause an effect at the receptor which is similar to the effect ofagonists, antagonists or partial agonists/antagonists. The compounds ofthe invention of the general formulae (I, Ia and Ib) are preferablyantagonists of the LHRH receptor (GnRH receptor).

Preferred compounds of the formulae (I, Ia and Ib) for the purposes ofthe present invention are those where X₁ is an S atom or S⁺—O⁻,preferably S atom, and R8 is an alkyl, arylalkyl or heteroarylalkylradical, where these radicals are optionally substituted by up to 3substituents independently selected from the group consisting of -Hal,—CN, —CO—O—R12, —CO—NR12R12′, —OH, —O—R13, —O—CO—R13, —O—SO₂—OR12,—O—SO₂—R12, —SO₂—OR12, —SO—R12, —O—PO(OR12)(OR12′), —O—PO(NR12R12′)₂,—O—CO—O—R13, —O—CO—NR12R12′, —O—CS—NR12R12′, —S—R12, —NR12R12′,—NH—CO—R13, —NH—SO₂—R12, —NH—CO—O—R13, —NH—CO—NHR12, —NH—C(NH)—NH₂,where R12, R12′ and R13 have the meanings indicated above.

Further preferred compounds of the formulae (I, Ia and Ib) for thepurposes of the present invention are those where

-   R10 is the radical —R11, —CO—R11, —CO—OR11, —CO—NHR11, —C(NH)—NHR11,    —SO₂—R1, or —SO₂NHR11,-   R11 is an arylalkyl or heteroarylalkyl radical which is substituted    in the aryl or heteroaryl group by one or more substituents    independently selected from the group consisting of Hal, —CN,    -alkyl, —CF₃, —OCF₃, —OH, —O-alkyl, and —O—(CH₂CH₂—O)_(n)—CH₃, and-   R8 is an alkyl, arylalkyl or heteroarylalkyl radical which is    optionally substituted by up to 3 substituents independently    selected from the group consisting of -Hal, —CN, —CO—O—R12,    —CO—NR12R12′, —OH, —O—R13, —O—CO—R13, —O—SO₂—OR12, —SO₂—OR12,    —O—SO₂—R12, —SO—R2, —O—PO(OR12)(OR12′), —O—PO(NR12R12′)₂,    —O—CO—O—R13, —O—CO—NR12R12′, —O—CS—NR12R12′, —S—R12, —NR12R12′,    —NH—CO—R13, —NH—SO₂—R12, —NH—CO—O—R13, —NH—CO—NHR12, —NH—C(NH)—NH₂,    -   where R12, R12′ and R13 have the meanings indicated above.

Further preferred compounds of the formulae (I, Ia and Ib) for thepurposes of the present invention are those where R8 is either—C₁-C₆-alkyl-aryl or —C₁-C₆-alkyl heteroaryl, where the aryl orheteroaryl group is substituted by one to three, preferably by one,substituents independently selected from the group consisting of—O—(CH₂CH₂—O)_(n)—CH₃, —O—CO—(CH₂CH₂—O)_(n)—CH₃, —O—SO₂—OR12,—O—SO₂—R12, —O—PO(OR12)(OR12′), —O—PO(NR12R12′)₂, —O—CO—OR13,—O—CO—NR12R12′, and —O—CS—NR12R12′, where R12, R12′ and R13 have themeanings indicated above.

In a preferred variant of the present invention, at least one,preferably two of the radicals R4, R5, R6, and R7, preferably R5 and R7,are not hydrogen atoms. The radicals R5 and R7 are in particularselected independently of one another from the group consisting of —H,-Hal, —CN, —CF₃, —O-alkyl and —OCF₃, and are preferably —H, -Hal or—CF₃. Particularly preferred compounds are those in which R4 and R6 areeach a hydrogen atom, R5 is either —H or -Hal, and R7, independently ofR5, is either -Hal or —CF₃.

Further preferred compounds of the formulae (I, Ia and Ib) for thepurposes of the present invention are those where X₂ and X₃ are each O.

In a preferred variant of the present invention, R3 is a C₁-C₆-alkylradical, preferably a C₁-C₄-alkyl radical.

Preferred compounds for the purposes of the present invention are thosewhere R1, R2, R9 and also R12 and R12′, if present, are each a hydrogenatom.

Further preferred compounds of the general formulae (I, Ia and Ib) arethose in which R13 is a phenyl-C₁-C₄-alkyl radical, or the group—(CH₂CH₂—O)—CH₃.

In preferred compounds of the formulae (I, Ia and Ib), R10 has themeaning —CO—R11, —CO—OR11 or R11, where R11 has the meanings indicatedabove.

Further preferred compounds of the general formulae (I, Ia and Ib) arethose in which R11 is a phenyl-C₁-C₄-alkyl radical, preferably a benzylor phenylethyl radical, which is substituted in the phenyl groupoptionally by one to three, preferably one or two, substituentsindependently selected from the group consisting of -Hal, —C₁-C₄-alkyl,—CF₃, —OCF₃, —OH, —O—C₁-C₄-alkyl and —O—(CH₂CH₂—O)_(n)—CH₃.

Compounds of the general formulae (I, Ia and Ib) of particular interestfor the purposes of the present invention are those where

-   X₁ is either O, S or S⁺—O⁻,-   X₂ and X₃ are each O,-   R1 and R2 are each a hydrogen atom,-   R3 is a C₁-C₆-alkyl radical, preferably a C₁-C₄-alkyl radical,-   R4 and R6 are each a hydrogen atom,-   R5 is either a hydrogen atom or Hal,-   R7 is either Hal or —CF₃,-   R9 is a hydrogen atom,-   R10 is the radical —CO—R11 or —CO—OR11 or the radical R11,-   R11 is a phenyl-C₁-C₄-alkyl radical, preferably a benzyl or    phenylethyl radical, which is substituted in the phenyl group    optionally by one to three, preferably one or two, substituents    independently selected from the group consisting of -Hal,    —C₁-C₄-alkyl, —CF₃, —OCF₃, —OH, —O—C₁-C₄-alkyl and    (CH₂CH₂—O)_(n)—CH₃, and-   R8 is a phenyl-C₁-C₄-alkyl radical, preferably a benzyl or    phenylethyl radical, which is substituted in the phenyl group by a    substituent selected from the group consisting of    —O—(CH₂CH₂—O)_(n)—CH₃, —O—CO—(CH₂CH₂—O)_(n)—CH₃, and    —O—PO(OR12)(OR12′), —O—CO—OR13, or,    -   where, however, at least    -   (i) X₁ is S, or    -   (ii) R11 is a phenyl-C₁-C₄-alkyl radical, preferably a benzyl or        phenylethyl radical, which is substituted in the phenyl group by        at least one of the abovementioned substituents, i.e.        independently selected from the group consisting of -Hal,        —C₁-C₄-alkyl, —CF₃, —OCF₃, —OH, —O—C₁-C₄-alkyl and        —O—(CH₂CH₂—O)_(n)—CH₃,    -   R8 is also a C₁-C₆-alkyl, preferably a C₁-C₄-alkyl radical, or a        phenyl-C₁-C₄-alkyl radical, preferably a benzyl or phenylethyl        radical, the radicals optionally being substituted by a        substituent selected from the group consisting of —OH, —O—R13,        and —NR12R12′;-   R12, R12′ are independently of one another H, or a C₁-C₄-alkyl,    benzyl or phenylethyl radical, preferably H;-   R13 is selected from a C₁-C₄-alkyl, phenyl-C₁-C₄-alkyl, and phenyl    radical, or is the group —(CH₂CH₂—O), —CH₃, and is preferably a    benzyl or phenethyl radical, and    -   n is an integer from 1 to 6, preferably from 1 to 4.

Further preferred compounds of the invention of the general formulae (I,Ia and Ib) are those in which the radical X₁ is a sulfur atom.

In particular, the following compounds of the general formula (I), or(1-a) or (1-b), are to be regarded as particularly preferred:

Compounds in which X₁ is S or S⁺—O—, preferably S, R3 and R8 are each aC₁-C₄-alkyl radical, R4 and R6 are each a hydrogen atom, R5 and R7 areeach Hal, or R5 is a hydrogen atom and R7 is the group —CF₃, R10 is theradical —CO—R11, R11 is a benzyl or phenylethyl radical which issubstituted in the phenyl group by one or two substituents independentlyselected from the group consisting of -Hal, —OCF₃, and —OCH₃.

Compounds in which X₁ is O, R3 is a C₁-C₄-alkyl radical, R4 and R6 areeach a hydrogen atom. R₅ and R₇ are each Hal, or R₅ is a hydrogen atomand R7 is the group —CF₃. R10 is the radical —CO—R11 or —CO—OR11 or theradical R11, R11 is a benzyl or phenylethyl radical which is substitutedin the phenyl group by one or two Hal atoms, and R8 is a C₁-C₄-alkyl,benzyl or phenylethyl radical, where the phenyl radical is optionallysubstituted by —OH.

Compounds in which X₁ is S or S⁺—O⁻, preferably S, R3 is a C₁-C₄-alkylradical, R4 and R6 are each a hydrogen atom, R5 and R7 are each Hal, R10is the radical —CO—OR1, R11 is a benzyl or phenylethyl radical which issubstituted in the phenyl group where appropriate by one or two Halatoms, and R8 is a C₁-C₄-alkyl, benzyl or phenylethyl radical, where thephenyl radical is optionally substituted by —OH.

Compounds in which X₁ is O or S or S⁺—O⁻, preferably O or S. R3 is aC₁-C₄-alkyl radical, R4 and R6 are each a hydrogen atom, R5 and R7 areeach Hal, or R5 is a hydrogen atom and R7 is the group —CF₃, R10 is theradical —CO—R11 or —CO—OR11, R11 is a benzyl or phenylethyl radicalwhich is substituted in the phenyl group where appropriate by one or twoHal atoms, and R8 is a benzyl or phenylethyl radical which issubstituted in the phenyl group by a —O—PO(OH); radical.

The most preferred compounds of the general formula (I) are thefollowing:

-   4-chlorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylpropyl}carbamate    (1),-   4-chlorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (2),-   4-chlorobenzyl    {(S)-1-[(R)-3-((S)-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (3).-   (R)-6,8-dichloro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (4).-   (R)-6,8-dichloro-3-{(S)-2-[2-(3-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (5),-   2-chlorobenzyl    {(S)-1-[(R)-3-((S)-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (6),-   benzyl    {(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (7),-   benzyl    4-{(S)-3-benzyloxycarbonylamino-3-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]propyl}phenylcarbonate    (8),-   benzyl    [(S)-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-(4-phosphonooxyphenyl)ethyl]carbamate    (9).-   benzyl    [(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]carbamate    (10),-   benzyl    [(S)-1-[(R)-3-((S)-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-phosphonooxyphenyl)propyl]-carbamate    (11),-   benzyl    [(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-phosphonooxyphenyl)propyl]carbamate    (12),-   (R)-6,8-dichloro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (13),-   (R)-6,8-dichloro-3-[(S)-2-[2-(2-fluorophenyl)acetylamino]-4-(4-hydroxyphenyl)butyrylamino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoyl-butyl)amide (14),-   mono(4-{(S)-3-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-[2-(2-fluorophenyl)acetylamino]-propyl}phenyl    phosphate (15),-   (R)-6,8-dichloro-3-((S)-2-[3-(4-fluorophenyl)propionylamino]-3-methylpentanoylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylpropyl)amide (16),-   (S)-5-[(R)-3-((S)-1-carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-5-[3-(4-fluorophenyl)propionylamino]pentylammonium    trifluoroacetate (17),-   (S)-6,8-dichloro-3-{(S)-2-[3-(2-hydroxyphenyl)propionylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (18),-   benzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-[4-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)phenyl]ethyl}carbamate    (19).-   (R)-6,8-dichloro-3-((S)-2-{3-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)phenyl]propionylamino}-3-methylpentanoylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (20),-   (R)-6,8-dichloro-3-((S)-2-{2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)phenyl]acetylamino}-3-methylpentanoylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (21),-   (R)-6,8-dichloro-3-[(S-2-[3-(2-fluorophenyl)propionylamino]-4-(4-hydroxyphenyl)butyrylamino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (22).-   (R)-6,8-dichloro-3-{(S)-2-[3-(2-fluorophenyl)propionylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (23),-   benzyl    {(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-[4-(2-{2-[2-(2-methoxyethoxy)ethoxy]-ethoxy}ethoxy)phenyl]propyl}carbamate    (24),-   benzyl    {(S)-1-[(R)-8-chloro-6-fluoro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (25),-   3-methylbenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (26),-   2,6-difluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (27),-   3,5-difluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (28),-   3,5-dichlorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (29),-   3-fluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (30),-   2-fluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (31),-   3-chlorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (32),-   3,5-difluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (33),-   3-fluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (34),-   2-fluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (35).-   3-fluorobenzyl    [(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]-carbamate    (37),-   2-fluorobenzyl    [(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]-carbamate    (38),-   2-(2-fluorophenyl)ethyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (40).-   2-fluorobenzyl    {(S)-1-[(R)-8-chloro-6-fluoro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}-carbamate    (41),-   3-fluorobenzyl    {(S)-1-[(R)-8-chloro-6-fluoro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (42),-   2-fluorobenzyl    [(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]-carbamate    (43),-   3-fluorobenzyl    [(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]-carbamate    (45),-   3-methoxybenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (47),-   4-fluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (48),-   2-methylbenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (49),-   2,3-dimethoxybenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (50).-   2-methoxybenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (51),-   (R)-6,8-dichloro-3-{(S)-2-[2-(2-fluorophenyl)ethylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (52),-   2-trifluoromethylbenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (53),-   3-trifluoromethylbenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (54),-   3-trifluoromethoxybenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (55).-   2-trifluoromethoxybenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (56),-   4-fluorobenzyl    {(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (57),-   (R)-6,8-dichloro-3-((S)-2-[2-(4-fluorophenyl)ethylamino]-3-methylpentanoylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (58),-   (R)-6,8-dichloro-3-{(S)-2-[2-(2,6-difluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (59),-   4-fluorobenzyl    {(S)-1-[(R)-8-chloro-6-fluoro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (60),-   (R)-6,8-dichloro-3-{(S)-2-[2-(3-fluorophenyl)ethylamino]-3-methylpentanoylamino}-6-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid {(S)-1-carbamoyl-2-methylbutyl}amide (61),-   (R)-8-chloro-3-{(S)-2-[2-(2,6-difluorophenyl)acetylamino]-3-methylpentanoylamino}-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (62),-   (R)-8-chloro-6-fluoro-3-{(S)-2-[2-(4-fluorophenyl)ethylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (63),-   4-fluorobenzyl    {(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate    (64),-   (R)-8-chloro-6-fluoro-3-{(S)-2-[2-(4-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (65).-   (R)-8-chloro-3-{(S)-2-[2-(2,4-difluorophenyl)acetylamino]-3-methylpentanoylamino}-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (66),-   (R)-8-chloro-6-fluoro-3-{(S)-2-[2-(4-fluorophenyl)ethylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (67),-   (R)-8-chloro-6-fluoro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (68),-   (R)-8-chloro-6-fluoro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (69).-   (R)-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-cyclopropyl-1-thiocarbamoylethyl)amide (70).-   (R)-3-{(S)-2-[2-(2,6-difluorophenyl)acetylamino]-3-methylpentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-cyclopropyl-1-thiocarbamoylethyl)amide (71),-   (R)-8-chloro-6-fluoro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-cyclopropyl-1-thiocarbamoylethyl)amide (72),-   (R)-3-{(S)-2-[2-(2,6-difluorophenyl)acetylamino]-3-methylpentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (73),-   (R)-3-(S)-2-[2-(2,6-difluorophenyl)acetylamino]-3-methylpentanoylamino)-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (74),-   (R)-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-1-carbamoyl-2-methylbutyl)amide (75),-   (R)-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (76).-   (R)-8-chloro-3-{(S)-2-[2-(2,6-difluorophenyl)acetylamino]-3-methylpentanoylamino}-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic    acid ((S)-2-cyclopropyl-1-thiocarbamoylethyl)amide (77).

The abovementioned compounds 4, 7, 11, 12, 13, 14, 15, 30, 31, 34, 37,45, 48, 52, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75 and 76 are moreover very particularly preferred.

The novel tetrahydrocarbazole derivatives of the invention of thegeneral formulae (I, Ia and Ib) as defined above are GPCR ligands. Thus,the aforementioned compounds of the invention are suitable for thetreatment and prophylaxis of pathological states mediated by GPCR, andof pathological states which can be influenced by modulation of thisreceptor, and thus treated. The compounds of the invention can beemployed in particular for the inhibition, i.e. as antagonist, of theLHRH receptor or of receptors of the neurokinin family, especially theNK₁ and/or NK2 receptor, and are thus suitable for example for thetreatment of benign and malignant neoplastic diseases, for the treatmentand prevention of nausea and vomiting, for example as a consequence ofemetogenic chemotherapy, for the treatment of pain, inflammations andrheumatic and arthritic pathological conditions, in male fertilitycontrol, for hormone therapy, in hormone replacement therapy and for thetreatment and/or control of female sub- or infertility.

In male fertility control, the compounds of the invention bring about areduction in spermatogenesis. Combined administration with androgens,e.g. testosterone or testosterone derivatives, such as, for example,testosterone esters, is preferred. The testosterone derivatives can inthis case be administered for example by injection, e.g. byintramuscular depot injection.

The compounds of the invention of the general formulae (I, Ia and Ib)can also be employed in female hormone therapy, for example for thetreatment of benign hormone-dependent disorders such as endometriosis,uterine fibroids, uterine myomas (uterine leiomyomas), endometriumhyperplasia, dysmenorrhea, and dysfunctional uterine bleeding(menorrhagia, metrorrhagia), where appropriate in combination with otherhormones, e.g. estrogens or/and progestins. Particularly preferred arecombinations of the LHRH receptor antagonists of the invention andtissue-selective partial estrogen agonists such as Raloxifene®.

The compounds of the invention can also be employed in hormonereplacement therapy, for example for treating hot flushes.

The compounds of the invention of the general formulae (I, Ia and Ib)can moreover be employed to control female fertility, for example byswitching off the endogenous hormone cycle for controlled induction ofovulation (“COS=controlled ovarian stimulation”), and for the treatmentof sterility within the scope of assisted reproduction techniques suchas in-vitro fertilization (“IVF”).

On the other hand, the novel compounds of the invention of the generalformulae (I, Ia and Ib) are also suitable for female contraception.Thus, an LHRH receptor antagonist of the invention can be administeredon days 1 to 15 of the female cycle together with estrogen, preferablywith very low estrogen dosages. On days 16 to 21 of the cycle of intake,progestagen is added to the combination of estrogen and LHRH receptorantagonist. The LHRH receptor antagonist of the invention can beadministered continuously throughout the cycle. It is possible in thisway to achieve a reduction in the hormone dosage and thus a reduction inthe side effects of nonphysiological hormone levels. It is additionallypossible to achieve advantageous effects in women suffering frompolycystic ovary syndrome and androgen-dependent disorders such as acne,seborrhea and hirsutism. An improved cycle control compared withprevious administration methods is also to be expected.

Further indications are benign prostate hyperplasia (BPH), gonadalprotection during chemotherapy, developmental disturbances in earlychildhood, e.g. pubertas praecox, the treatment of HIV infections orAIDS and of neurological or neurodegenerative disorders, ARC (AIDSrelated complex), Kaposi sarcoma, tumors originating in the brain and/ornervous system and/or meninges (cf. WO 99/01764), dementia andAlzheimer's disease.

Finally, the compounds of the invention of the general formulae (I, Iaand Ib) as defined above can also be employed for the treatment ofmalignant hormone-dependent neoplastic diseases such as premenopausalbreast cancer, prostate cancer, ovarian cancer, uterine cancer, cervicalcancer and endometrial cancer, since they suppress endogenous sexsteroid hormones, and in addition are also suitable for the treatmentand prevention of nausea and vomiting, for example resulting fromemetogenic chemotherapy, or for the treatment of pain, inflammations andrheumatic and arthritic pathological conditions.

The novel compounds of the invention of the general formulae (I, Ia andIb) as defined above are suitable as GPCR ligands, in particular LHRHreceptor antagonists or antagonists of receptors of the neurokininfamily, for the treatment of the aforementioned pathological conditionsfor administration to mammals and in particular humans, but also forveterinary medical purposes. e.g. in domestic and productive animals,but also in wild animals.

The administration can take place in a known manner, for example orallyor non-orally, in particular topically, rectally, intravaginally,nasally or by injections or implantation. Oral administration ispreferred.

The novel compounds of the invention of the general formulae (I, Ia andIb) are converted into a form which can be administered and are mixedwhere appropriate with pharmaceutically acceptable carriers or diluents.Suitable excipients and carriers are described for example in Ullman'sEncyclopedia of Technical Chemistry, Vol. 4, (1953), 1-39; Journal ofPharmaceutical Sciences, Vol. 52 (1963), 918 et seq.; H. v.Czetsch-Lindenwald. “Hilfsstoffe für Pharmazie and angrenzende Gebiete”;Pharm. Ind. 2, 1961, 72 et seq., Dr. H. P. Fiedler, “Lexikon derHilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete”, Cantor KG, Aulendorf in Wurttemberg, 1971.

Oral administration can take place for example in solid form as tablet,capsule, gel capsule, coated tablet, granulation or powder, but also inthe form of a drinkable solution. The novel compounds of the inventionof the general formulae (I, Ia and Ib) as defined above can for oraladministration be combined with known and ordinarily used,physiologically tolerated excipients and carriers such as, for example,gum arabic, talc, starch, sugars such as, for example, mannitol,methylcellulose, lactose, gelatin, surface-active agents, magnesiumstearate, cyclodextrins, aqueous or nonaqueous carriers, diluents,dispersants, emulsifiers, lubricants, preservatives and flavorings (e.g.essential oils). The compounds of the invention can also be dispersed ina microparticulate, e.g. nanoparticulate, composition.

Non-oral administration can take place for example by intravenous,subcutaneous, intramuscular injection of sterile aqueous or oilysolutions, suspensions or emulsions, by means of implants or byointments, creams or suppositories. Administration as sustained releaseform is also possible where appropriate. Implants may comprise inertmaterials, e.g. biodegradable polymers or synthetic silicones such as,for example, silicone rubber.

Intravaginal administration is possible for example by means of vaginalrings. Intrauterine administration is possible for example by means ofdiaphragms or other suitable intrauterine devices. Transdermaladministration is additionally provided, in particular by means of aformulation suitable for this purpose and/or suitable means such as, forexample, patches.

As already explained above, the novel compounds of the invention of thegeneral formulae (I, Ia and Ib) can also be combined with other activepharmaceutical ingredients. It is possible for the purposes of thecombination therapy to administer the individual active ingredientssimultaneously or separately, in particular either by the same route(e.g. orally) or by separate routes (e.g. orally and as injection). Theymay be present and administered in identical or different amounts in aunit dose. It is also possible to use a particular dosage regimen whenthis appears appropriate. It is also possible in this way to combine aplurality of the novel compounds of the invention of the generalformulae (I, Ia and Ib) with one another.

The dosage may vary within a wide range depending on the type ofindication, or the severity of the disorder, the mode of administration,the age, gender, bodyweight and sensitivity of the subject to betreated. It is within the ability of a skilled worker to determine a“pharmacologically effective amount” of the combined pharmaceuticalcomposition. Administration can take place in a single dose or aplurality of separate dosages.

A suitable unit dose is, for example, from 0.001 mg to 100 mg of theactive ingredient, i.e. at least one compound of the invention of thegeneral formulae (I, Ia and Ib) and, where appropriate, a further activeingredient, per kg of a patient's bodyweight.

A further aspect of the present invention accordingly includespharmaceutical compositions as described above, comprising one or moreof the novel compounds of the invention of the general formulae (I, Iaand Ib) as defined above and, where appropriate, pharmaceuticallyacceptable carriers and/or excipients. Preferred and particularlypreferred pharmaceutical compositions are those comprising at least oneof the novel compounds of the invention of the general formulae (I, Iaand Ib) mentioned above as preferred or particularly preferred, inparticular at least one of the compounds 1 to 77 specifically mentionedabove, with very particular preference for compounds 4, 7, 11, 12, 13,14, 15, 30, 31, 34, 37, 45, 48, 52, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75 and 76 in this connection. Inpharmaceutical compositions of the present invention it is possible,besides at least one compound of the general formulae (I, Ia and Ib) asdefined above, for other active pharmaceutical ingredients also to bepresent, as already detailed above.

In the pharmaceutical compositions of the invention, at least one of thenovel compounds of the invention (I) as defined above are present in apharmacologically effective amount, preferably in a unit dose, e.g. theaforementioned unit dose, specifically and preferably in anadministration form which makes oral administration possible.

The present invention additionally provides in a further aspectcompounds of the general formulae (I, Ia and Ib) as defined above foruse as medicaments. As already explained above, the compounds of thegeneral formulae (I, Ia and Ib) act as GPCR ligands, in particular asantagonists of the LHRH receptor, and are thus particularly suitable foruse as medicaments. The compounds of the invention of the generalformulae (I, Ia and Ib) for use as medicaments are preferably providedfor administration for the treatment or alleviation of theaforementioned medical indications or for contraception.

Preferred tetrahydrocarbazole compound of the invention of the generalformulae (I, Ia and Ib) as defined above for use as medicaments are inturn the compounds which have been mentioned above as preferred andparticularly preferred compounds, especially the preferred compounds ofthe invention 1 to 77 specifically mentioned and, unless alreadyincluded therein, the compounds of the invention mentioned in theexamples.

Concerning the pharmaceutical compositions comprising compounds of theinvention of the general formulae (I, Ia and Ib), and concerning the useof the compounds of the invention of the general formulae (I, Ia and Ib)as medicaments, reference may be made to that already said in connectionwith the use of the novel compounds of the invention of the generalformulae (I, Ia and Ib) themselves, in relation to possible uses andadministrations.

In another aspect, the present invention also provides the use of atleast one tetrahydrocarbazole compound of the invention of the generalformulae (I, Ia and Ib) as defined above for producing a medicament forthe treatment of GPCR-mediated diseases, where the GPCR receptor ispreferably the LHRH receptor, and the compounds of the inventionpreferably act as LHRH receptor antagonists.

Accordingly, in a further aspect, the present invention provides the useof at least one compound of the invention of the general formulae (I, Iaand Ib) as defined above, or of a corresponding pharmaceuticalcomposition, for producing a medicament which acts as LHRH receptorantagonist, preferably for the treatment of benign and malignantneoplastic diseases, for male fertility control, for hormone therapy,for hormone replacement therapy, for controlled ovarian stimulation inthe context of in-vitro fertilization (IVF), for the treatment and/orcontrol of female sub- and infertility and for female contraception.Hormone therapy in this connection includes, inter alia, the treatmentof endometriosis, uterine leiomyomas, uterine fibroids and benignprostate hyperplasia (BPH). Concerning further indications andexplanations of the indications relating to the current aspect of thepresent invention, reference may be made to the statements made aboveconcerning the first aspect of the present invention, i.e. to thecompounds of the invention of the general formulae (I, Ia and Ib)themselves, and the explanations given there.

The compounds of the invention are not only suitable for the treatmentor therapy of said pathological conditions, but are equally suitable forthe prevention or prophylaxis, and the alleviation (e.g. throughsuppressing the symptoms) of these pathological conditions or diseases.

The present invention provides in a further aspect the use of a compound(I) of the invention for producing a medicament for the treatment ofbenign and malignant neoplastic diseases, and for hormone treatment.Preferred and particularly preferred compounds of the invention for thisuse are the compounds which have already been mentioned at the outset aspreferred or particularly preferred compounds of the invention of thegeneral formulae (I, Ia and Ib) themselves as defined above. Veryparticularly preferred compounds are also the compounds 1 to 77 whichare specifically mentioned hereinabove.

The present invention likewise provides a process for producing amedicament for the treatment of GPCR-mediated pathological conditions,the process being characterized by the use of at least one compound ofthe invention of the general formulae (I, Ia and Ib) or of acorresponding pharmaceutical composition. The explanations given aboveconcerning the preferred and particularly preferred compounds of theinvention, and concerning the specific pathological conditions which canbe treated, prevented or alleviated by the pharmaceutical compositionproduced with use of the compounds of the invention are also to be citedfor this aspect of the present inventor.

In addition, the present invention provides a method for male fertilitycontrol or for female contraception, comprising the administration of anamount, effective for male fertility control or for femalecontraception, of at least one compound of the invention of the generalformulae (I, Ia and Ib), where appropriate in combination with a furtheractive ingredient, to a subject, preferably a mammal and particularlypreferably a human The explanations given above concerning furtheraspects of the present invention in relation to preferred andparticularly preferred compounds of the invention, and the explanationsin relation to dosage, administration etc. likewise apply here.

In a further aspect, the present invention relates to a method for thetreatment of GPCR-mediated pathological conditions. The method comprisesthe administration of at least one compound (I) of the invention asdefined above in a pharmaceutically effective amount to a mammal and inparticular to a human, in cases where such a treatment is necessary. Asalready explained above concerning the novel compounds (I) of theinvention, and the pharmaceutical compositions of the invention, itrests with the expert knowledge of a skilled worker to determine apharmaceutically effective amount, depending on the specificrequirements of the individual case. The preferred administration formis oral administration. Administration of one or more of the compounds(I) of the invention in combination with at least one further activeingredient, as already explained above, is also provided. Theexplanations given concerning the above aspects of the present inventionrelating to preferred and particularly preferred compounds and to thespecific pathological conditions which can be treated, alleviated orprevented also apply to the treatment method mentioned herein.Particularly preferred compounds for this aspect are also compounds I to77.

In addition, the present invention also relates to a method forinhibiting GPCRs, in particular the LHRH receptor or a receptor of theneurokinin family, in a patient, comprising the administration of apharmaceutically effective amount of at least one compound of thegeneral formulae (I, Ia and Ib) as defined above, where appropriate incombination with a further active ingredient as defined above, to apatient (mammal and in particular human) requiring such a treatment. Thepreferred and particularly preferred compounds of the invention of thegeneral formulae (I, Ia and Ib) are once again identical to thepreferred and particularly preferred compounds mentioned aboveconcerning the other aspects of the present invention, especially thecompounds 1 to 77. The explanations above concerning the pathologicalconditions which can be treated by administration of the compounds ofthe invention, preferably through their LHRH receptor antagonisticeffect, also apply to the treatment method of the invention describedherein.

The compounds of the invention of the general formulae (I, Ia and Ib) asdefined above can be prepared for example in the following way:

Firstly, the compounds of the invention can be synthesized by preparingthe depicted central tetrahydrocarbazole structure

where this optionally protected tetrahydrocarbazole structure alreadycontains the substituents R₄ to R₇—where appropriate as precursors or inprotected form.

The central tetrahydrocarbazole structure is obtainable, for example, bya Fischer indole synthesis, known per se. For this purpose, a suitablysubstituted cyclohexanone derivative which is provided where appropriatewith protective groups is condensed with the particular desiredphenylhydrazine derivative which is likewise suitably substituted and,where appropriate, provided with protective groups (e.g. as described byBritten & Lockwood, J. Chem. Soc. Perkin Trans. I 1974, 1824 or Maki etal., Chem. Pharm. Bull. 1973, 21, 240). The cyclohexane structure issubstituted in the 4,4′ position by the radicals —COOH and —NH, or whereappropriate by the (protected) precursors thereof. The phenylhydrazinestructure is substituted where appropriate by the radicals R⁴ to R⁷.Phenylhydrazine derivatives which are not commercially available can beprepared by processes known to the skilled worker. Positional isomersresulting where appropriate in the condensation of the cyclohexanonederivative and the phenylhydrazine derivative can be separated bychromatographic methods such as, for example, HPLC.

The radicals R₁₀R₉NCHR₈CX₃NH— and R₁R₂NCX₁CHR₃NHCX₂— can in principle beintroduced and modified in various ways depending on their nature byprocesses known to the skilled worker, as indicated for example in WO03/051837 by means of examples and general explanations.

Another process for synthesizing the compounds of the invention of thegeneral formulae (I, Ia and Ib) is the following:

Firstly a basic tripeptide structure is prepared by coupling threesuitable amino acids, the first amino acid AA¹ comprising the radical R3as side chain and the third amino acid AA³ comprising the radical R8 ora precursor of R8 as side chain, while the “middle” amino acid AA² is3-amino-2,3,4,9-tetrahydro-1-H-carbazole-3-carboxylic acid (abbreviatedto Thc). The basic Thc structure can be correspondingly substituted,depending on the substitution pattern of the desired resulting compoundof the invention, by the radicals R4 to R7, where appropriate in theform of their precursors or in protected form. The peptide coupling canbe carried out by processes known to the skilled worker, e.g. in thesolid or liquid phase. Modifications of the substitution pattern canthen be undertaken, such as “deprotection” of particular radicals.

The following scheme illustrates the coupling of the amino acids forexample on the solid phase:

where R* is —CO—O-benzyl (i.e. Z) or any protective group, e.g. Fmoc,where R8* is either —C₁-C₆-alkylaryl or —C₁-C₆-alkylheteroaryl, wherethe aryl or heteroaryl group is substituted by up to three, preferablyby one, OH group, or R8* may also—corresponding to the definitions givenfor R8— have the meaning of R3.

This process is illustrated in detail below for the example ofsolid-phase and liquid-phase syntheses and for the specific examples 1to 77.

General Methods for Synthesizing the Compounds of the Invention of theGeneral Formulae (I, Ia and Ib)

The compounds of the invention of the formulae (I, Ia and Ib) aresynthesized either by conventional synthesis in solution or else whollyor partly on a solid phase.

Method 1A Solid-Phase Synthesis of LHRH Peptidomimetics

The specific syntheses of the compounds detailed in the examples tookplace on a solid phase using the semiautomatic SP 650 synthesizer (fromLabortec). The standard program is shown in Table 1 below:

TABLE 1 Program for SP 650 synthesizer (from Labortec) Time in StepFunction Solvent/reagent min Repetitions 1 wash DMF 2 2 2 eliminate 20%piperidine + 1% DBU 5 3 3 wash DMF 2 2 4 wash 2-propanol 2 1 5 wash DMF2 2 6 wash 2-propanol 2 1 7 wash DMF 2 2 8 STOP 9 addition Fmoc-AA +HOBt + DIC 10 skip 11 coupling 120-300 1 12 wash DMF 2 1 13 wash2-propanol 2 1 14 wash DMF 2 1 15 wash 2-propanol 2 1 16 wash DMF 2 1 17wash 2-propanol 2 1 18 END

Elimination of the Fmoc protective group takes place in this case with20% piperidine and 1% DBU in DMF for 5 minutes. The procedure is carriedout a total of three times for 5 minutes each time.

DMF and 2-propanol are used as washing solutions.

Coupling of the first Fmoc-amino acid takes place with HOBt and DIC inDCM and DMF (v/v=1.1).

Coupling of the further Fmoc-amino acids is carried out with HATU andHOAt (0.5M solution in DMF) in the presence of DIPEA.

Method 1Aa Coupling of the First Amino Acid AA¹ (Synthesis ofFmoc-AA¹-Resin)

Pretreat 1 mmol of Fmoc-resin[Fmoc-2,4-dimethoxy-4′-(carboxymethyloxy)benzhydrylamine linked toaminomethyl-substituted polystyrene resin (200-400 mesh; 0.55 mmol/g]according to synthesizer program, eliminate Fmoc protective group, add 1mmol of Fmoc-amino acid AA¹ (Fmoc-NH—CHR3—COOH), 2 mmol of HOBt in DCMand DMF (v/v=1:1) and 3 mmol of DIC, shake at RT for 3 h and then washaccording to program.

Method 1Ab Coupling of the Second Amino Acid AA² (Synthesis ofFmoc-AA²-AA¹-Resin)

Pretreat 1 mmol of Fmoc-AA¹-resin according to program, add 2 mmol ofFmoc-amino acid AA² (Fmoc-Thc-OH), 2 mmol of HATU, 2 mmol of HOAt (0.5Msolution in DMF) and 5 mmol of DIPEA and shake at RT for 4-6 h. Checkthe pH during the reaction and adjust to pH 8-9 by adding DIPEA. Aftercoupling is complete, washing steps according to program.

Method 1Ac Coupling of the Third Amino Acid AA³ (Synthesis ofZ-AA³-AA²-AA¹-Resin)

Pretreat 1 mmol of Fmoc-AA²-AA¹-resin according to program, add 2 mmolof Z-amino acid Z-AA³ (benzyl-O—CO—NH—CHR8*-COOH), 2 mmol of HATU. 2mmol of HOAt (0.5M solution in DMF) and 5 mmol of DIPEA and shake at RTfor 46 h. Check the pH during the reaction and adjust to pH 8-9 byadding DIPEA. After coupling is complete, washing steps according toprogram.

Method 1Ad Coupling of the Third Amino Acid AA³ (Synthesis ofFmoc-AA³-AA²-AA¹-Resin)

Pretreat 1 mmol of Fmoc-AA²-AA¹-resin according to program, add 2 mmolof Fmoc-amino acid AA³ (Fmoc-NH—CHR8*-COOH), 2 mmol of HATU, 2 mmol ofHOAt (0.5M solution in DMF) and 5 mmol of DIPEA and shake at RT for 4-6h. Check the pH during the reaction and adjust to pH 8-9 by addingDIPEA. After coupling is complete, washing steps according to program.

Method 1Ae Modification of Fmoc-AA³-AA²-AA¹-Resin: Introduction of aTerminal Z Residue (Reaction with Z-Cl)

Pretreat 1 mmol of Fmoc-AA³-AA²-AA¹-resin according to program, shake 2mmol of Z-chloride, 4 mmol of DIPEA and catalytic amounts of DMAP for 3h and then washing steps according to program.

Method 1Af Introduction of a Terminal Residue R10 where R10 is—CO—R11-Reaction with R11-COOH

Pretreat 1 mmol of Fmoc-AA³-AA²-AA¹-resin according to program, shake 3mmol of carboxylic acid R11-COOH, 3 mmol of HOBt and 4 mmol of DIC for 3h and then washing steps according to program.

Method 1Ag Introduction of a Terminal Residue R10 where R10 is —CO—OR11,and if Appropriate Modification of R8* to R8-Reaction with R-OSu

Pretreat 1 mmol of Fmoc-AA³-AA²-AA¹-resin according to program, shake 3mmol of R-OSu, 5 mmol of DIPEA and catalytic amounts of DMAP for 3 h andthen wash according to program. If R8* has a free OH group, conversionof this OH group to —O—CO—O—R13 is possible, in which case R11 and R13are identical radicals.

Method 1Ah Introduction of a Terminal Radical R10 were R10 is—R11-Reaction with R10-Iodide (R10-I)

Pretreat 1 mmol of Fmoc-AA³-AA²-AA¹-resin according to program, shake 1mmol of R10-I. 3 mmol of sodium bicarbonate for 3 h and then washaccording to program.

Method 1Ba Introduction of the Phosphoric Acid Residue onto the OH Groupof hTyr, for Example, in the Side Chain R8*

Wash 1 mmol of R10-AA³-AA²-AA¹-resin 2× with DCM, suspend in DCM, add 2mmol of phosphoric acid bis(dimethylamide) chloride. 2 mmol of DMAP and3 mmol of DBU or DIPEA and shake at RT for 4-6 h, and then washaccording to program.

Method 1Bb Introduction of Fmoc-Tyr-(PO(OBzl)-OH)—OH

Pretreat 1 mmol of Fmoc-AA²-AA¹-resin according to program, add 2 mmolof Fmoc-Tyr(PO(OBzl)-OH)—OH, 2 mmol of HATU, 2 mmol HOAt (0.5M solutionin DMF) and 5 mmol of DIPEA and shake at RT for 3 h. Check the pH duringthe reaction and adjust to pH 8-9 by adding DIPEA. After the coupling iscomplete, washing steps according to program.

Method 2 Solid-Phase Synthesis of Thioamides

The synthesis is based on, for example, H. Takuta et al. J. Org. Chem.1989, 54, 4812 and Majer et al. Biochem & Biophys. Res. Commun. 1988,150, 1017.

The first coupling takes place by method 1Aa.

Conversion of the carboxamide to the thioamide takes place withLawesson's reagent in the following way: stir 1 mmol of Fmoc-AA-resinand 24 mmol of Lawesson's reagent in 20 ml of dry tcluene at a bathtemperature of 90-100° C. for 7 h, filter off the resin with suction andwash on the funnel 5× alternately with DCM and hot MeOH.

The subsequent coupling of the second and third amino acids takes placeby methods 1Ab-g and 1B.

Method 3A Elimination of the Carboxamides from the Resin

The peptide-resin is dried in vacuo at max. 40° C. before theelimination. Typically, 10-15 ml of elimination solution are used pergram of peptide.

1 mmol of peptide-resin is for this purpose stirred in a mixture of 0.5ml of water and 15 ml of TFA at a bath temperature of 40° C. for 2 h.The resin is filtered off with suction and washed with a little TFA, andthe resulting TFA solution is concentrated under diaphragm pump vacuum.

The oily crude product is purified by preparative HPLC—see method 4.

Method 3B Elimination of the Thioamides from the Resin

The peptide-resin is dried in vacuo at max. 40° C. before theelimination. Normally 10-15 ml of cleavage solution are used per gram ofpeptide.

Addition of EDT as scavenger is necessary in the elimination of thethioamides.

1 mmol of peptide-resin is stirred in a mixture of 0.5 ml of water/0.5ml of EDT/15 ml of TFA at a bath temperature of 40-50° C. for 2-3 h. Theresin is filtered off with suction and washed with a little TFA, and theresulting TFA solution is concentrated under diaphragm pump vacuum. Thecrude product is purified by preparative HPLC—see method 4.

Method 3C Elimination of a Carboxamide from the Resin and SimultaneousHydrolysis of the Phosphoric Acid bis(dimethylamide) Residue

Analogous to Method 3A.

For complete hydrolysis, after a reaction time of 2 h a further 1 ml ofwater is added and stirring is continued at 40° C. for 60 min. The resinis then filtered off with suction and washed with a little TFA, andfinally the TFA solution is concentrated under diaphragm pump vacuum.The crude product is purified by preparative HPLC—see method 4.

Method 3D Elimination of a Thioamide from the Resin and SimultaneousHydrolysis of the Phosphoric Acid bis(dimethylamide) Residue

Analogous to Method 3B.

For complete hydrolysis, after a reaction time of 2-3 h a further 1 mlof water is added and stirring is continued at 40° C. for 60 min. Theresin is then filtered off with suction and washed with a little TFA,and finally the TFA solution is concentrated under diaphragm pumpvacuum. The crude product is purified by preparative HPLC—see method 4.

Method 4 Purification of the Crude Products by Semipreparative HPLC

Analytical and semipreparative HPLC systems from Shimadzu; column250-50, LiChrospher® 100, RP18 (12 μm) from Merck; flow rate 60 inml/min.

Eluents: A=970 ml of water+30 ml of ACN+1 ml of TFA

-   -   B=300 ml of water+700 ml of ACN+1 ml of TFA        UV detector 220 nm.

All products are isolated by gradient elution.

The crude products are dissolved in eluent B (DMF added for products oflow solubility) and purified in portions on the column (e.g. dissolve500 mg of crude product in 15 ml of B and separate in one portion). Theseparation conditions in this case depend on the peptide sequence andnature and amount of the impurities and are established experimentallybeforehand on the analytical column.

A typical gradient is: 60%-100% B in 30 minutes.

If the crude products are mixtures of diastereomers, they are separatedby this method.

The isolated fractions are checked by analytical HPLC ACN and TFA areremoved in a rotary evaporator, and the remaining aqueous concentrate islyophilized.

Method 5 Liquid-Phase Synthesis of benzyl{(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl-carbamoyl]-2-methylbutyl}carbamate(7)Method 5A Synthesis of tert-butyl{(5)-1-carbamoyl-2-methylbutyl}carbamate (Boc-Ile-NH₂)

10 mmol of (S)—H-Ile-NH₂ hydrochloride were mixed with 20 mmol ofaqueous sodium carbonate solution. A solution of 11 mmol of Boc₂O indioxane was slowly added dropwise to the aqueous solution at RT, and thereaction mixture was stirred at RT for a further 60 min. Theprecipitated crude product was then filtered off with suction, suspendedin water and adjusted to an acidic pH by dropwise addition of 20%strength hydrochloric acid. The crude product was again filtered offwith suction, washed with water and dried over P₄O₁₀ in vacuo at 50° C.

Yield 85%, m p. 167° C. (lit. 166° C.)

Method 5B Synthesis of tert-butyl((S)-2-methyl-1-thiocarbamoylbutyl)carbamate (Boc-Ile thioamide)

The synthesis was based on, for example, H. Takuta et al. J. Org. Chem.1989, 54, 4812 and Majer et al. Biochem & Biophys. Res. Commun. 1988,150, 1017.

10 mmol of (S)-Boc-Ile-NH2 were suspended in 50 ml of THF, 6 mmol ofLawesson's reagent were added, and the mixture was stirred at RT for 20h. The suspension became a clear solution. The reaction solution wasfinally concentrated under diaphragm pump vacuum.

The crude product was purified by column chromatography (DCM+ethylacetate=9:1)

Yield 88 9% m p. 131° C. (lit. 132° C.)

Method 5C Synthesis of (S)-2-amino-3-methylpentanamide (H-Ile thioamide)

10 mmol of (S)-Boc-Ile thioamide were stirred in 40 ml of DCM and 10 mlof TFA at RT for 4 h. The reaction solution was finally concentratedunder diaphragm pump vacuum, and the resulting residue was mixed with 50ml of water, adjusted to pH 8 with conc. ammonia solution and finallyextracted 5× with ethyl acetate. The combined organic extracts werewashed with saturated sodium chloride solution, dried over sodiumsulfate and filtered, and the filtrate was concentrated under diaphragmpump vacuum.

Yield 87.5% (yellow solid)

Method 5D Synthesis of(R/S)-3-(S)-2-benzyloxycarbonylamino-3-methylpentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid (Z-(S)-Ile-(R/S)-(6,8-Cl)-Thc-OH)

10 mmol of (R/S)—H-(6,8-Cl)-Thc. 12 mmol of (S)-Z-Ile-OSu, 30 mmol ofDIPEA and a spatula tip of DMAP were put into 50 ml of DMF and stirredat a bath temperature of 80° C. for 4 h. The reaction mixture was thenconcentrated under diaphragm pump vacuum, and the residue was mixed withwater, acidified with dilute hydrochloric acid and extracted with ethylacetate. The organic phase was then washed with saturated sodiumchloride solution, dried over sodium sulfate and filtered, and thefiltrate was concentrated under diaphragm pump vacuum.

Yield 119 g of diastereomer mixture (1:1 mixture)

Method 5E Synthesis of benzyl{(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate(7) ((S)-Z-Ile-(R)-(6,8-Cl)-Thc-(S)-Ile thioamide)

3 mmol of Z-Ile-(R/S)-(6,8-Cl)-Thc-OH, 3 mmol of H—(S)-Ile thioamide, 3mmol of HATU and 15 mmol of DIPEA were heated in 5 ml of DMF in amicrowave at max. 100° C. and max. 150 watt for 3 min. The reactionsolution was diluted with eluent B and separated in 2 portions on apreparative HPLC column (see method 4).

Yield of diastereomer 1=19% of HPLC purity 98.5% (compound 7)

Yield of diastereomer 2=17.7% of HPLC purity 95%

Method 6 Exemplary Synthesis of C-Terminal Substituted Amides inSolution—(S)-2-{[(R/S)-3-((S)-2-benzyloxycarbonylamino-3-methylpentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3-carbonyl]amino}-3-methylpentanoicacid ((S)-Z-Ile-(R/S)-(6,8-Cl)-Thc-(S)-Ile-OH)+R1-NH—R2

1 mmol of (S)-Z-Ile-(R/S)-(6,8-Cl)-Thc-(S)-Ile-OH (*) are suspended in 5ml of DMF, and 1.1 mmol of R1-NH—R2, 1.2 mmol of PyBOP and 3 mmol of NMMare added, and the mixture is stirred at RT for 16 h. The reactionmixture is concentrated under diaphragm pump vacuum and purified bypreparative HPLC (see method 4). The product obtained here is(S)-Z-Ile-(R/S)-(6,8-Cl)-Thc-(S)-Ile-NR1R2.

(*) The synthesis of (S)-Z-Ile-(R/S)-(6,8-Cl)-Thc-(S)-Ile-OH can becarried out on a solid phase with 2-chlorotrityl chloride-resin (1.37mmol/g—Alexis Biochemicals 120-002-0000). The first coupling is carriedout in DCM in the presence of DIPEA, and the second and third couplingsin analogy to methods 1Ab+1Ac−1Ag. Elimination takes place as in method3A, and purification as in method 4.

Method 7 Reaction of Lawesson's Reagent with R10-AA³-AA²-AA¹-NH₂Alternative Method for Thiation of Sequences with C-Terminal AmideFunction when AA² is a Thc-Building Block

1 mmol of R10-AA³-AA²-AA¹-NH₂ are dissolved in 40 ml of dry toluene, 1mmol of Lawesson's reagent is added at RT, the suspension is stirred ata bath temperature of 80° C. for 3-4 h, and the reaction mixture isconcentrated under diaphragm pump vacuum. The residue is fractionated bypreparative HPLC in analogy to method 4.

Method 8 Preparation of Alkyl Aryl Ethers by Mitsunobu Reaction

Alkyl aryl ethers are prepared from corresponding OH compounds withaddition of PPh₃ and DEAD (Mitsunobu et al., J. Am. Chem. Soc. 1972, 94,679).

The general mode of preparation of the inventions of the invention issummarized once again below, indicating the appropriate process stepsand methods:

a) firstly the Fmoc-protected AA¹ is coupled by method 1Aa to the resin

b) where appropriate conversion into a thioamide takes place in a secondstep by method 2

c) The product obtained from step a or b is, after elimination of theprotective group, reacted with the protected amino acid 2, theappropriately substituted Thc derivative, by method 1Ab:

d) Then the product obtained from step c is, after elimination of theprotective group, reacted with the third protected AA:

-   where R*=Z=-CO—O-benzyl (in method 1Ac) or R*=Fmoc (in method 1Ad),    and R8* is —C₁-C₆-alkyl-aryl or —C₁-C₆-alkyl-heteroaryl, where the    aryl or heteroaryl group is substituted by up to three, preferably    by one OH group, or R8* may also—in accordance with the definitions    given for R8— have the meaning of R3.    e) Where R*=Fmoc, the product obtained in step d is initially    deprotected and the terminal free amino group is then reacted so as    to introduce the radical R10:

Depending on the nature of R10, different processes are used:

-   -   (i) method 1Af for R10=-CO—R11; reaction with R11—COOH    -   (ii) method 1Ag for R10=-CO—OR11; reaction with R11—OSu; in this        case it is likewise possible, if R8* has a free OH group, for        this OH group to be converted into —O—CO—O—R13, in which case        R11 and R13 are identical radicals    -   (iii) method 1Ah for R10=—R11; reaction with R10-iodide (R10-I)        f) In the optional step f it is possible where appropriate also        to convert R8* into R8, e.g. by    -   (i) introducing a phosphoric acid radical into R8 by converting        an OH group as in step method 1Ba; or    -   (ii) introducing a —CO—O-benzyl radical (Z) into R8 by        converting an OH group as in step method 1Ae;        g) The tripeptide is then eliminated from the resin by one of        methods 3A, 3B, 3C or 3D, and is purified by method 4.        h) If further modifications of R8 or R11 are also necessary,        these can take place now, e.g. introduction of alkyl ethers from        the corresponding OH compounds as in step method 8.

The compounds of the invention mentioned in Examples 1 to 15 and 16 to77 were prepared as indicated in detail below by methods 1-8 as definedabove. The analytical characterization of the compounds of the inventiontook place by ¹H-NMR spectroscopy and/or mass spectrometry.

The chemicals and solvents employed were obtained commercially fromusual suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster,Maybridge, Merck, Sigma, TCI etc.) or synthesized by processes known tothe skilled worker

For the exemplary embodiments indicated below, chiral building blockswere usually employed in enantiopure form. In the case of thetetrahydrocarbazole precursor, the racemic building block was employed.Final products were purified by semipreparative HPLC and characterizedin the form of the pure diastereomers.

The compounds of the invention of the general formulae (I, Ia and Ib),especially compounds 1 to 77, were named using the AutoNom 2000 software(ISIS™/Draw 2.5; MDL).

The invention is to be explained in detail by means of the followingexamples without, however, being restricted to these examples.

LIST OF ABBREVIATIONS USED

-   e.g. for example-   DBU 1.8-diazabicyclo[5.4.0]undec-7-ene-   HOBt 1-hydroxybenzotriazole-   Fmoc 9-fluoroenylmethoxycarbonyl-   Boc tert-butyloxycarbonyl-   Z benzyloxycarbonyl-   Z-Cl benzyloxycarbonyl chloride-   Boc₂O di-ter-butyl dicarbonate-   Bzl benzyl-   AA amino acid-   EDT 1,2-ethanedithiol-   DEAD diethyl azodicarboxylate-   DIC N,N′-diisopropylcarbodiimide-   DCC N,N′-dicyclohexylcarbodiimide-   HATU N,N,N,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium    hexafluorophosphate-   HOAT 1-hydroxy-7-azabenzotriazole-   PyBop (benzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate-   OSu N-hydroxysuccinimidyl-   DIPEA diisopropylethylamine-   DMAP N,N′-dimethylaminopyridine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   NMM N-methylmorpholine-   TFA trifluoroacetic acid-   DCM dichloromethane-   DMF N,N′-dimethylformamide-   DMA N,N′-dimethylacetamide-   ACN acetonitrile-   THF tetrahydrofuran-   Me methyl-   MeOH methanol-   Lawesson's reagent    2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide-   Thc 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid-   Ala alanine(yl)-   Val valine(yl)-   Ile isoleucine(yl)-   Leu leucine(yl)-   Gln glutamine(yl)-   Asn asparagine(yl)-   Tyr tyrosine(yl)-   hTyr homo-tyrosine(yl)-   Arg arginine(yl)-   Lys lysine(yl)-   RT room temperature-   m.p. melting point-   ml milliliter-   min minute-   h hour-   ELISA enzyme linked immunosorbent assay-   HEPES N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid-   DMEM Dulbecco's modified Eagles medium-   RIA radio immuno assay-   LHRH luteinizing hormone releasing hormone-   LH luteinizing hormone-   NK1 neurokinin 1-   NK2 neurokinin 2

EXAMPLES I. Synthesis of Compounds of the Invention Example 14-Chlorobenzyl{(S)-1-[(R)-3-((S)-1-carbamoyl-Z-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylpropyl}carbamate(1)

0 275 g of 1 was obtained starting from 3 mmol of resin. Fmoc-Val-OH(AA¹ and AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and 4-chlorobenzyl2,5-dioxopyrrolidin-1-yl carbonate by general methods 1Aa, b, d, g, 3Aand 4.

Yield: 0 275 g (14.44% of theory)

¹H-NMR (DMSO-d6, 300K. 500 MHz):

δ=11 33 (s, 1H); 7.40-7.02 (m, 10H); 4.94 (d, 1H); 4.75 (d, 1H); 4.15(dd, 1H); 3.87 (dd, 1H); 3.02 (d, 1H); 2.87 (d, 1H); 2.82-2.68 (m, 2H);2 12 (m, 1H); 1 95 (m, 1H); 1.87 (m, 1H), 0 88-0.72 (m, 12H) ppm

ESI-MS: found: 664.1 (M+H⁺)/calculated: 663 g/mol

Example 2 4-Chlorobenzyl{(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate(2)

0.190 g of 2 was obtained starting from 2.5 mmol of resin, Fmoc-Val-OH(AA¹), Fmoc-Ile-OH (AA³), Fmoc-(6,8-dichloro)-Thc-OH (MA) and4-chlorobenzyl 2,5-dioxopyrrolidin-1-yl carbonate by general methods1Aa, b, d, g, 3A and 4.

Yield: 0.190 g (10.64% of theory)

¹H-NMR (DMSO-d6, 300K, 500 MHz):

δ=11 33 (s, 1H); 7 38-7 03 (m, 9H); 4.94 (d, 1H); 4.7 (d, 1H); 4.15 (dd,1H); 3.87 (dd, 1H), 2 98 (d, 1H); 2 88 (d, 1H); 2.78-2 55 (m, 3H), 2.1(m, 1H); 1 95 (m, 1H); 1.62 (m, 1H), 1 33 (m, 1H); 1.03 (m, 1H); 0.75(m, 12H) ppm

ESI-MS: found: 678.2 (M+H⁺)/calculated: 677 g/mol

Example 3 4-Chlorobenzyl {(S)-1-[(R)-3-((S)carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate(3)

0 155 g of 3 was obtained starting from 2.5 mmol of resin, Fmoc-Ile-OH(AA¹ and AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and 4-chlorobenzyl2,5-dioxopyrrolidin-1-yl carbonate by general methods 1Aa, b, d, g, 3Aand 4.

Yield: 0 155 g (8.85% of theory)

¹H-NMR (DMSO-d6, 300K, 500 MHz):

δ=11 35 (s, 1H, indole NH); 7.4-7.03 (3m, 4H, 3H, 3H); 4.96, 4.7 (2d,2H, C₅H₆—CH ₂); 4 18 (dd, 1H); 3 89 (dd, 1H); 2 98, 2.88 (2d, 2H, CH₂);2.77, 2.71, 2.62, 2.12 (4m, 4H, CH ₂—CH ₂); 1 82 (m, 1H); 1 64 (m, 1H);1.45-1.3 (m, 2H); 1.05 (m, 2H), 0.84 (d, 3H, CH3); 0 82 (d, 3H, CH₃);0.79 (t, 3H, CH₃); 0.73 (t, 3H, CH₃) ppm

ESI-MS: found: 692 2 (M+H⁺)/calculated: 691 g/mol

Example 4(R)-6,8-Dichloro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid ((S)-1-carbonyl-2-methylbutyl)amide (4)

0.995 g of 4 was obtained starting from 7.0 mmol of resin, Fmoc-Ile-OH(AA¹ and AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and 2-fluorophenylaceticacid by general methods 1Aa, b, d, f, 3A and 4.

Yield: 0 995 g (19.64% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHZ):

δ=11.35 (s, 1H, indole NH); 8.12 (s, 1H); 7.82 (d, 1H); 7 40 (s, 1H);7.29-7 23 (m, 2H); 7.20-7.13 (m, 3H); 7.12-7.06 (m, 3H); 4.12 (m, 2H);3.47, 3.21 (2d, 2H, CH2); 2.99, 2 94 (2d, 2H, CH2); 2.79, 2.68 (2m, 2H,CH2); 2.59 (m, 1H); 2.12 (m, 1H); 1.62 (m, 2H); 1.33 (m, 2H); 1.01 (m,2H); 0.80-0.71 (4m, 12H, 4 CH3) ppm

ESI-MS: found: 660.3 (M+H⁺)/calculated: 659.251 g/mol

Example 5(R)-6,8-Dichloro-3-{(S)-2-[2-(3-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid ((S)-1-carbamoyl-2-methylbutyl)amide (5)

0 185 g of 5 was obtained starting from 3.0 mmol of resin, Fmoc-Ile-OH(AA¹ and AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and 3-fluorophenylaceticacid by general methods 1Aa, b, d, f, 3A and 4.

Yield: 0.185 g (11% of theory)

¹H-NMR (DMSO-d6, 300K, 500 MHz):

δ=11.2 (s, 1H, indole NH); 8.17 (d, 1H, NH); 8.07 (s, 1H, NH); 7.36 (s,1H); 7 35-7 22 (m, 2H); 7.12-7.0 (m, 6H); 4.12-4 07 (m, 2H); 3.55, 3.45(2d, 2H, C₆H₅F—CH ₂); 3.4, 3 0 (2d, 2H, CH₂, Thc); 2.85 (m, 1H);2.75-2.68 (m, 1H); 2.35-2.28 (m, 1H); 2.1-2.0 (m, 1H); 1.65 (m, 1H);1.45 (m, 1H); 1.32 (m, 1H); 1.15-1.0 (m, 2H); 0.82-0.7 (m, 7H); 0.5-0.4(d, t, 6H, CH₃) ppm.

ESI-MS: found: 660.3 (M+H⁺)/calculated 659 g/mol

Example 6 2-Chlorobenzyl {(S)-1-[(R)-3-((S)carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate(6)

0 255 g of 6 was obtained starting from 3.0 mmol of resin, Fmoc-Ile-OH(AA¹ and AA³), Fmoc-(6,8-dichloro)-Thc-OH (AAM) and 2-chlorobenzyl2,5-dioxopyrrolidin-1-yl carbonate by general methods 1Aa, b, d, g, 3Aand 4

Yield: 0.255 g (14.72% of theory)

¹H-NMR (DMSO-d6, 300K, 500 MHz):

δ=11.35 (s, 1H, indole NH); 7.75 (s, 1H, NH); 7.4 (d, 1H, NH); 7.35-7.2(m, 6H); 7.1-7.05 (m, 2H); 5 05, 4.82 (2d, 2H, C₅H₆—CH ₂); 4.18 (dd,1H); 3.9 (dd, 1H); 2.98, 2.88 (2d, 2H, CH₂); 2 8, 2.72, 2.62, 2.12 (4m,4H, CH ₂—CH ₂); 1.75 (m, 1H); 1.62 (m, 1H); 1.45-1 25 (m, 2H); 1 05 (m,2H); 0.68 (m, 12H, CH₃) ppm.

ESI-MS: found: 692.2 (M+H⁺)/calculated: 691 g/mol

Example 7 Benzyl{(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate(7)

0.126 g of 7 was obtained starting from 5 0 mmol of resin, Fmoc-Ile-OH(AA¹). Z-Ile-OH (AA³) and Fmoc-(6,8-dichloro)-Thc-OH (AA²) and bygeneral methods 1Aa, 2, 1Ab, c, 3B and 4.

Yield: 0.126 g (3.38% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11.38 (s, 1H, indole NH); 9.71, 9.32 (2s, 2H, CS—NH ₂); 7.73 (s, 1H);7.36 (s, 1H); 7.30-7.11 (3m, 8H); 4.96, 4.69 (2d, 2H, C₅H₆—CH ₂); 4.46(dd, 1H); 3.89 (dd, 1H); 2.98, 2.88 (2d, 2H, CH₂); 2.77, 2.71, 2.62,2.12 (4m, 4H, CH ₂—CH ₂); 1.77 (m, 1H); 1 64 (m, 1H); 1.50 (m, 1H); 1 34(m, 1H); 1.04 (m, 2H); 0.84 (d, 3H, CH₂); 0.82 (d, 3H, CH₃); 0.79 (t,3H, CH₃); 0.73 (t, 3H, CH₃) ppm

ESI-MS: found: 674.2 (M+H⁺)/calculated: 673 g/mol

As explained above, compound 7 was also synthesized in liquid phase bymethod 5 (A-E).

Example 8 Benzyl4-{(S)-3-benzyloxycarbonylamino-3-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]propyl}phenylcarbonate (8)

0.125 g of 8 was obtained starting from 3.5 mmol of resin, Fmoc-Ile-OH(AA¹), Fmoc-hTyr-OH (AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and benzylchlorocarbonate by general methods 1Aa, b, d, e, 3A and 4.

Yield: 0.125 g (3.92% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11.41 (s, 1H, indole NH); 7.77 (s, 1H, NH); 7.54 (d, 1H); 7.48-7.29(m, 10H); 7.22-7.05 (3m, 9H); 5 25 (s, 2H, OCOOCH ₂—C₆H₅); 4 96, 4.68(2d, 2H, C₆H₅—CH ₂—OCON); 4 18 (dd, 1H); 3.92 (dt, 1H); 3.00, 2.92 (2d,2H, CH₂); 2.74 (m, 2H); 2.60 (m, 2H); 2.46 (m, 1H), 2.08 (m, 1H),1.79-170 (m, 3H); 1 37 (m, 1H); 1 01 (m, 1H); 0.83 (d, 3H, CH—CH ₃);0.73 (t, 3H, CH₂—CH ₃) ppm

ESI-MS: found: 856.1 (M+H⁺)/calculated: 855 g/mol

Example 9 Benzyl[(S)-1-[(R)-3-((S)-1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-(4-phosphonooxyphenyl)ethyl]carbamate(9)

0.112 g of 9 was obtained starting from 1.3 mmol of resin, Fmoc-Ile-OH(AA¹). Z-Tyr-OH (AA³) and Fmoc-(6,8-dichloro)-Thc-OH (AA²) by generalmethods 1Aa, b, c, 1Ba, 3C and 4

Yield: 0 112 g (9 98% of theory)

¹H-NMR (DMSO-d6, 300K. 600 MHz):

δ=11.39 (s, 1H, indole NH); 7.98 (s, 1H); 7.45 (d, 1H); 7.42 (s, 1H); 737 (s, 1H); 7.32-7 28 (m, 3H); 7.17-7.12 (m, 6H); 7.10 (m, 1H); 7.02 (d,2H); 4.90, 4.73 (2d, 2H, C₆H₅—CH ₂); 4 26 (m, 1H); 4.19 (m, 1H); 2.94(m, 2H); 2.83 (m, 1H); 2.73 (m, 1H); 2.63 (m, 2H); 2 20 (m, 1H); 2.06(m, 1H); 1.73 (m, 1H); 1.41 (m, 1H); 1.05 (m, 1H); 0.84 (d, 3H, CH—CH₃); 0 79 (t, 3H, CH₂—CH ₃) ppm

ESI-MS: found: 788.2 (M+H⁺)/calculated: 787 g/mol

Example 10 Benzyl[(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]carbamate(10)

0.45 g of 10 was obtained starting from 4 4 mmol of resin, Fmoc-Ile-OH(AA¹), Fmoc-hTyr-OH (AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and benzylchlorocarbonate by general methods 1Aa, 2, 1Ab, d, e, 3B and 4

Yield 0.45 g (19.47% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11 41 (s, 1H, indole NH), 9.71 (s, 1H, CS—NH—CH); 9.28, 9.12 (2s,CS—NH ₂); 7.67 (s, 1H); 7.41 (d, 2H); 7.37 (s, 1H), 7.32-7.28 (m, 4H);7.17-7.15 (m, 3H); 6.83 (d, 2H); 6.61 (d, 2H); 4.96, 4.65 (2d, 2H,C₆H₅—CH ₂); 4.44 (dd, 1H); 3.89 (dd, 1H), 3.02, 2.88 (2d, 2H, CH₂); 2.76(m, 2H); 2.62 (m, 1H); 2.46 (m, 1H); 2.35 (m, 1H); 2.09 (m, 1H);1.79-1.74 (m, 3H): 1.48 (m, 1H); 1.02 (m, 1H); 0.83 (d, 3H, CH—CH ₃);0.74 (1, 3H, CH₂—CH ₃) ppm

ESI-MS: found 738.1 (M+H⁺)/calculated: 737 g/mol

Example 11 Benzyl[(S)-1-[(R)-3-((S)-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-phosphonooxyphenyl)propyl]carbamate(11)

1.511 g of 11 were obtained starting from 10.0 mmol of resin,Fmoc-Ile-OH (AA¹), Z-hTyr-OH (AA³) and Fmoc-(6,8-dichloro)-Thc-OH (AA²)by general methods 1Aa, b, c, 1 Ba, 3C and 4.

Yield: 1.511 g (18.37% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11.39 (s, 1H, indole NH); 7.75 (s, 1H); 7.49 (d, 1H); 7.42 (s, 1H);7.35-7.30 (m, 4H); 7.21-7.16 (m, 3H); 7.14 (d, 1H); 7.11 (s, 1H); 7.02(m, 4H); 4.96, 4.69 (2d, 2H, C₆H₅—CH ₂); 4.18 (dd, 1H); 3.92 (dt, 1H);3.00, 2.94 (2d, 2H, CH₂); 2.75 (m, 2H); 2.56 (m, 1H); 2.43 (m, 2H); 2.09(m, 1H); 1.75 (m, 3H); 1.38 (m, 1H); 1.05 (m, 1H); 0.83 (d, 3H, CH—CH₃); 0.75 (t, 3H, CH₂—CH ₃) ppm

ESI-MS: found: 802.0 (M+H⁺)/calculated: 801 g/mol

Example 12 Benzyl[(S)-1-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-phosphonooxyphenyl)propyl]carbamate(12)

0.079 g of 12 was obtained starting from 10.0 mmol of resin, Fmoc-Ile-OH(AA¹), Fmoc-hTyr-OH (AA³), Fmoc-(6,8-dichloro)Thc-OH (AA²) and benzylchlorocarbonate by general methods 1Aa, 2, 1Ab, d, e, 1Ba, 3D and 4.

Yield: 0.079 g (0.96% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11.41 (s, 1H, indole NH); 9.70, 9.29 (2s, 2H, CS—NH ₂); 7.73 (s, 1H);7.44 (d, 1H); 7.37 (s, 1H); 7.33-7 27 (m, 4H); 7 20-7.14 (m, 3H); 7 07-703 (m, 4H); 4.96, 4.66 (2d, 2H, C₆H₅—CH ₂); 4.44 (dd, 1H); 392 (dt, 1H);301, 2.91 (2d, 2H, CH₂), 2.74 (m, 2H); 2 59 (m, 2H); 2.44 (m, 2H); 2.09(m, H), 1 79 (m, 2H); 1 48 (m, 1H); 1 03 (m, 1H); 0 83 (d, 3H, CH—CH ₃);0.75 (t, 3H, CH ₃) ppm

ESI-MS: found: 818.1 (M+H⁺)/calculated: 817 g/mol

Example 13(R)-6,8-Dichloro-3-{(S)-2-[2-(2-fluorophenyl)acetylamino]-3-methylpentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (13)

0.437 g of 13 was obtained starting from 4.00 mmol of resin, Fmoc-Ile-OH(AA¹ and AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and 2-fluorophenylaceticacid by general methods 1Aa, 2, 1Ab, d, f, 3B and 4.

Yield: 0.437 g (15 61% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11 37 (s, 1H, indole NH); 9.69, 9.21 (2s, 2H, CS—NH ₂); 8.06 (d, 1H);7 82 (s, 1H); 7 37 (s, 1H); 7 29-7.23 (m, 2H); 7.17 (m, 2H); 7.09 (m,2H); 4.46 (dd, 1H); 4.15 (dt, 1H); 3 45, 3 18 (2d, 2H, CH₂); 2.97, 2.89(2d, 2H, C₂); 2.77 (m, 1H); 2.68 (m, 1H); 2.56 (m, 1H), 2.12 (m, 1H);1.71-1.59 (m, 2H); 1 44 (m, 1H); 1.35 (m, 1H); 1.02 (m, 2H); 0.81 (d,3H, CH—CH ₃); 0.78-0.75 (m, 6H, 2 CH₃), 0.73 (t, 3H, CH—CH ₃) ppm

ESI-MS: found: 676.2 (M+H⁺)/calculated: 675 g/mol

Example 14(R)-6,8-Dichloro-3-[(S)-2-[2-(2-fluorophenyl)acetylamino]-4-(4-hydroxyphenyl)butyrylamino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylicacid ((S)-2-methyl-1-thiocarbamoylbutyl)amide (14)

0 632 g of 14 was obtained starting from 4.5 mmol of resin, Fmoc-Ile-OH(AA¹). Fmoc-hTyr-OH (AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and2-fluorophenylacetic acid by general methods 1Aa, 2, 1Ab, d, f, 3B and4.

Yield: 0.632 g (17.61% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11.37 (s, 1H, indole NH); 9.67, 9.14 (2s, 2H, CS—NH ₂); 9.13 (br.s,1H, OH); 8.29 (d, 1H); 7.84 (s, 1H); 7.38 (s, 1H); 7.31 (d, 1H); 7.26(m, 1H); 7.21-7.08 (2m, 4H); 6.79 (d, 2H); 6.60 (d, 2H); 4.43 (dd, 1H);4.13 (d, 1H); 3.45, 3.22 (2d, 2H, CH₂); 2.99, 2.96 (2d, 2H, CH₂);2.76-2.72 (m, 2H); 2.58 (m, 1H); 2.42 (m, 1H); 2.33 (m, 1H); 2.09 (m,1H); 1.75 (m, 2H); 1.65 (m, 1H); 1.42 (m, 1H); 0.99 (m, 1H); 0.79 (d,3H, CH₂—CH ₃); 0.73 (t, 3H, CH₂—CH ₃) ppm

ESI-MS: found: 740.2 (M+H⁺)/calculated: 739 g/mol

Example 15Mono-(4-{(S)-3-[(R)-6,8-dichloro-3-((S)-2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-[2-(2-fluorophenyl)acetylamino]-propyl}phenylphosphate (15)

0.129 g of 15 was obtained starting from 3.3 mmol of resin, Fmoc-Ile-OH(AA¹), Fmoc-hTyr-OH (AA³), Fmoc-(6,8-dichloro)-Thc-OH (AA²) and2-fluorophenylacetic acid by general methods 1Aa, 2, 1Ab, d, f, 1Ba, 3Dand 4.

Yield: 0.129 g (4.6% of theory)

¹H-NMR (DMSO-d6, 300K, 600 MHz):

δ=11.38 (s, 1H, indole NH); 9.7, 9.15 (2s, 2H, CS—NH ₂); 8.32 (d, 1H);7.9 (s, 1H); 7.38 (s, 1H); 7.33-7.0 (m, 11H); 4.42 (dd, 1H); 4.17 (d,1H); 3.47, 3.22 (2d, 2H, CH₂); 2.99, 2.96 (2d, 2H, CH₂); 2.77-2.67 (m,2H); 2.6-2.35 (m, 2H); 2.1 (m, 1H); 1.8 (m, 2H); 1.65 (m, 1H); 1.43 (m,1H); 0.99 (m, 1H); 0.79 (d, 3H, CH₂—CH ₃); 0.73 (t, 3H, CH₂—CH ₃) ppm.

ESI-MS: found: 820.0 (M+H⁺)/calculated: 819 g/mol

Data on further exemplary embodiments are compiled in Table 2 below:

TABLE 2 Exemplary embodiments with synthetic sequence and MS data ESI-MSSynthesis ESI-MS found No. AUTONOM name method calculated (M + H⁺) 16(R)-6,8-Dichloro-3-{(S)-2-[3-(4-fluoro- 1Aa, b, d, f, 659 660.3phenyl)propionylamino]-3-methyl- 3A, 4pentanoylamino}-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylpropyl)amide 17(S)-5-[(R)-3-((S)-1-Carbamoyl-2-methyl- 1Aa, b, d, f, 674 675.3propylcarbamoyl)-6,8-dichloro-2,3,4,9- 3A, 4tetrahydro-1H-carbazol-3-ylcarbamoyl]-5-[3-(4-fluorophenyl)propionylamino]- pentylammonium trifluoroacetate 18(S)-6,8-Dichloro-3-{(S)-2-[3-(2-hydroxy- 1Aa, b, d, f, 671 672.3phenyl)propionylamino]-3-methyl- 3A, 4pentanoylamino}-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 19 Benzyl{(S)-1-[(R)-3-((S)-1-carbamoyl-2- 1Aa, b, d, e, 897 898.3methylbutylcarbamoyl)-6,8-dichloro- 3A, 4, 8, 42,3,4,9-tetrahydro-1H-carbazol-3-yl-carbamoyl]-2-[4-(2-{2-[2-(2-methoxy-ethoxy)ethoxy]ethoxy}ethoxy)phenyl]- ethyl}carbamate 20(R)-6,8-Dichloro-3-((S)-2-{3-[2-(2-{2-[2-(2- 1Aa, b, d, f, 861 862.4methoxyethoxy)ethoxy]ethoxy}ethoxy)- 3A, 4, 8, 4phenyl]propionylamino}-3-methyl- pentanoylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S)-1- carbamoyl-2-methylbutyl)amide 21(R)-6,8-Dichloro-3-((S)-2-{2-[2-(2-{2-[2-(2- 1Aa, b, d, f, 847 848.4methoxyethoxy)ethoxy]ethoxy}ethoxy)- 3A, 4, 8, 4phenyl]acetylamino}-3-methylpentanoyl-amino)-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid((S)-1-carbamoyl-2-methyl- butyl)amide 22(R)-6,8-Dichloro-3-[(S)-2-[3-(2-fluoro- 1Aa, b, d, f, 737 738.3phenyl)propionylamino]-4-(4-hydroxy- 3A, 4phenyl)butyrylamino]-2,3,4,9-tetrahydro- 1H-carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 23(R)-6,8-Dichloro-3-{(S)-2-[3-(2-fluoro- 1Aa, b, d, f, 673 674.4phenyl)propionylamino]-3-methyl- 3A, 4pentanoylamino}-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 24 Benzyl{(S)-1-[(R)-6,8-dichloro-3-((S)-2- 1Aa, 2, 1Ab, 928 928.2methyl-1-thiocarbamoylbutylcarbamoyl)- d, g, 3B, 4,2,3,4,9-tetrahydro-1H-carbazol-3-yl- 8, 4carbamoyl]-3-[4-(2-{2-[2-(2-methoxy-ethoxy)ethoxy]ethoxy}ethoxy)phenyl]- propyl}carbamate 25 Benzyl{(S)-1-[(R)-8-chloro-6-fluoro-3-((S)- 5 (A-E) 657 658.32-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl- carbamoyl]-2-methylbutyl}carbamate26 3-Methylbenzyl {(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 671 672.2carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 27 2,6-Difluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 693 694.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 28 3,5-Difluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 693 694.4carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 29 3,5-Dichlorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 725 726.2carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 30 3-Fluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 675 676.4carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 31 2-Fluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 675 676.4carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 32 3-Chlorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 691 694.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 33 3,5-Difluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 677 678.3carbamoyl-2-methylbutylcarbamoyl)-8- 3A, 4chloro-6-fluoro-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 34 3-Fluorobenzyl {(S)-1-[(R)-3-((S)-1- 1Aa, b, d,g, 659 660.4 carbamoyl-2-methylbutylcarbamoyl)-8- 3A, 4chloro-6-fluoro-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-2-methyl-butyl}carbamate 35 2-Fluorobenzyl {(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g,659 660.4 carbamoyl-2-methylbutylcarbamoyl)-8- 3A, 4chloro-6-fluoro-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-2-methyl-butyl}carbamate 36 4-[(S)-3-[(R)-3-((S)-1-Carbamoyl-2-methyl- 1Aa, b, d,g, 927 928.2 butylcarbamoyl)-6,8-dichloro-2,3,4,9-tetra- 3A, 4hydro-1H-carbazol-3-ylcarbamoyl]-3-(2,6-difluorobenzyloxycarbonylamino)propyl]- phenyl 2,6-difluorobenzylcarbonate 37 3-Fluorobenzyl [(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 739740.4 carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]- carbamate 38 2-Fluorobenzyl[(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 739 740.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]- carbamate 394-[(S)-3-[(R)-3-((S)-1-Carbamoyl-2-methyl- 1Aa, b, d, g, 891 892.4butylcarbamoyl)-6,8-dichloro-2,3,4,9-tetra- 3A, 4hydro-1H-carbazol-3-ylcarbamoyl]-3-(2-fluorobenzyloxycarbonylamino)propyl]- phenyl 2-fluorobenzyl carbonate 402-(2-Fluorophenyl)ethyl {(S)-1-[(R)-3-((S)- 1Aa, b, d, g, 689 690.31-carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl})carbamate 41 2-Fluorobenzyl{(S)-1-[(R)-8-chloro-6- 1Aa, 2, 1Ab, 675 676.4fluoro-3-((S)-2-methyl-1-thiocarbamoyl- d, g, 3A, 4butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}- carbamate 42 3-Fluorobenzyl{(S)-1-[(R)-8-chloro-6- 1Aa, 2, 1Ab, 675 676.4fluoro-3-((S)-2-methyl-1-thiocarbamoyl- d, g, 3A, 4butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}- carbamate 43 2-Fluorobenzyl[(S)-1-[(R)-6,8-dichloro-3- 1Aa, 2, 1Ab, 755 756.4((S)-2-methyl-1-thiocarbamoylbutyl- d, g, 3A, 4carbamoyl)-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-3-(4-hydroxy-phenyl)propyl]carbamate 44 4-[(S)-3-[(R)-6,8-Dichloro-3-((S)-2-methyl-1Aa, 2, 1Ab, 907 908.3 1-thiocarbamoylbutylcarbamoyl)-2,3,4,9- d, g, 3A,4 tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(2-fluorobenzyloxycarbonylamino)- propyl]phenyl 2-fluorobenzyl carbonate45 3-Fluorobenzyl [(S)-1-[(R)-6,8-dichloro-3- 1Aa, 2, 1Ab, 755 756.3((S)-2-methyl-1-thiocarbamoylbutyl- d, g, 3A, 4carbamoyl)-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-3-(4-hydroxy-phenyl)propyl]carbamate 46 4-[(S)-3-[(R)-6,8-Dichloro-3-((S)-2-methyl-1Aa, 2, 1Ab, 907 908.4 1-thiocarbamoylbutylcarbamoyl)-2,3,4,9- d, g, 3A,4 tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(3-fluorobenzyloxycarbonylamino)- propyl]phenyl 3-fluorobenzyl carbonate47 3-Methoxybenzyl {(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 687 688.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 48 4-Fluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 675 676.4carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 49 2-Methylbenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 671 672.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 50 2,3-Dimethoxybenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 717 718.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 51 2-Methoxybenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 687 688.3carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 52 (R)-6,8-Dichloro-3-{(S)-2-[2-(2-1Aa, b, d, h, 645 646.3 fluorophenyl)ethylamino]-3- 3A, 4methylpentanoylamino}-2,3,4,9-tetrahydro- 1H-carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 53 2-Trifluoromethylbenzyl{(S)-1-[(R)-3-((S)- 1Aa, b, d, g, 725 726.41-carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 54 3-Trifluoromethylbenzyl{(S)-1-[(R)-3-((S)- 1Aa, b, d, g, 725 726.41-carbamoyl-2-methylbutylcarbamoyl)-6,8- 3A, 4dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 55 3-Trifluoromethoxybenzyl{(S)-1-[(R)-3- 1Aa, b, d, g, 741 742.3 ((S)-1-carbamoyl-2-methylbutyl-3A, 4 carbamoyl)-6,8-dichloro-2,3,4,9-tetra-hydro-1H-carbazol-3-ylcarbamoyl]-2- methylbutyl}carbamate 562-Trifluoromethoxybenzyl {(S)-1-[(R)-3- 1Aa, b, d, g, 741 742.3((S)-1-carbamoyl-2-methylbutyl- 3A, 4 carbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2- methylbutyl}carbamate 574-Fluorobenzyl {(S)-1-[(R)-6,8-dichloro-3- 1Aa, 2, 1Ab, 691 692.3((S)-2-methyl-1-thiocarbamoylbutyl- d, g, 3A, 4carbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}- carbamate 58(R)-6,8-Dichloro-3-{(S)-2-[2-(4-fluoro- 1Aa, b, d, h, 645 647.1phenyl)ethylamino]-3-methylpentanoyl- 3A, 4amino}-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid((S)-1-carbamoyl-2- methylbutyl)amide 59(R)-6,8-Dichloro-3-{(S)-2-[2-(2,6- 1Aa, b, d, f, 677 678.5difluorophenyl)acetylamino]-3- 3A, 4methylpentanoylamino}-2,3,4,9-tetrahydro- 1H-carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 60 4-Fluorobenzyl{(S)-1-[(R)-8-chloro-6- 1Aa, 2, 1Ab, 675 676.4fluoro-3-((S)-2-methyl-1-thiocarbamoyl- d, g, 3A, 4butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}- carbamate 61(R)-6,8-Dichloro-3-{(S)-2-[2-(3- 1Aa, b, d, h, 645 646.3fluorophenyl)ethylamino]-3- 3A, 4methylpentanoylamino}-2,3,4,9-tetrahydro- 1H-carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 62(R)-8-Chloro-3-{(S)-2-[2-(2,6-difluoro- 1Aa, 2, 1Ab, 677 678.4phenyl)acetylamino]-3-methylpentanoyl- d, f, 3A, 4amino}-6-fluoro-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-methyl- 1-thiocarbamoylbutyl)amide 63(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(4- 1Aa, b, d, h, 629 630.4fluorophenyl)ethylamino]-3-methyl- 3A, 4pentanoylamino}-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-1- carbamoyl-2-methylbutyl)amide 64 4-Fluorobenzyl{(S)-1-[(R)-3-((S)-1- 1Aa, b, d, g, 659 660.3carbamoyl-2-methylbutylcarbamoyl)-8- 3A, 4chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}- carbamate 65(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(4- 1Aa, 2, 1Ab, 659 660.3fluorophenyl)acetylamino]-3- d, f, 3A, 4methylpentanoylamino}-2,3,4,9-tetrahydro- 1H-carbazole-3-carboxylic acid((S)-2- methyl-1-thiocarbamoylbutyl)amide 66(R)-8-Chloro-3-{(S)-2-[2-(2,4-difluoro- 1Aa, 2, 1Ab, 677 678.2phenyl)acetylamino]-3-methylpentanoyl- d, f, 3A, 4amino}-6-fluoro-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-methyl- 1-thiocarbamoylbutyl)amide 67(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(4- 1Aa, b, d, h, 645 646.4fluorophenyl)ethylamino]-3-methyl- 2, 3A, 4pentanoylamino}-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-methyl- 1-thiocarbamoylbutyl)amide 68(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2- 1Aa, 2, 1Ab, 659 660.4fluorophenyl)acetylamino]-3-methyl- d, f, 3A, 4pentanoylamino}-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-methyl- 1-thiocarbamoylbutyl)amide 69(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro- 1Aa, b, d, f, 643 644.4phenyl)acetylamino]-3-methylpentanoyl- 3A, 4amino}-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid((S)-1-carbamoyl-2-methyl- butyl)amide 70(R)-3-{(S)-2-[2-(2-Fluorophenyl)acetyl- 1Aa, 2, 1Ab, 673 674.2amino]-3-methylpentanoylamino}-8- d, f, 3A, 4trifluoromethyl-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-cyclo- propyl-1-thiocarbamoylethyl)amide 71(R)-3-{(S)-2-[2-(2,6-Difluorophenyl)acetyl- 1Aa, 2, 1Ab, 691 692.3amino]-3-methylpentanoylamino}-8- d, f, 3A, 4trifluoromethyl-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-cyclo- propyl-1-thiocarbamoylethyl)amide 72(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro- 1Aa, 2, 1Ab, 657 658.2phenyl)acetylamino]-3-methylpentanoyl- d, f, 3A, 4amino}-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid((S)-2-cyclopropyl-1-thio carbamoylethyl)amide 73(R)-3-{(S)-2-[2-(2,6-Difluorophenyl)acetyl- 1Aa, 2, 1Ab, 693 694.3amino]-3-methylpentanoylamino}-8-tri- d, f, 3A, 4fluoromethyl-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-methyl- 1-thiocarbamoylbutyl)amide 74(R)-3-{(S)-2-[2-(2,6-Difluorophenyl)acetyt- 1Aa, b, d, f, 677 678.2amino]-3-methylpentanoylamino}-8-tri- 3A, 4fluoromethyl-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S)-1-carbamoyl-2-methylbutyl)amide 75 (R)-3-{(S)-2-[2-(2-Fluorophenyl)acetyl-1Aa, b, d, f, 659 660.4 amino]-3-methylpentanoylamino}-8-tri- 3A, 4fluoromethyl-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S)-1-carbamoyl-2-methylbutyl)amide 76 (R)-3-{(S)-2-[2-(2-Fluorophenyl)acetyl-1Aa, 2, 1Ab, 675 676.4 amino]-3-methylpentanoylamino}-8-tri- d, f, 3A, 4fluoromethyl-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-methyl- 1-thiocarbamoylbutyl)amide 77(R)-8-Chloro-3-{(S)-2-[2-(2,6-difluoro- 1Aa, 2, 1Ab, 675 676.3phenyl)acetylamino]-3-methylpentanoyl- d, f, 3A, 4amino}-6-fluoro-2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid((S)-2-cyclo- propyl-1-thiocarbamoylethyl)amide

II. Demonstration of the LHRH Antagonistic Effect of Compounds of theInvention II.1A LHRH Receptor-Ligand Binding Assay (MembranePreparations from Rat Pituitary Cells) Assay

Heterologous competition experiments were carried out using membranepreparations from rat pituitary cells which naturally strongly expressthe LHRH receptor. The ligand used in this case was [¹²⁵I][D-Trp⁶]-LHRHin a concentration of 0.05 nM. Unlabeled [D-Trp⁶]-LHRH was used in aconcentration of 1 μM, or the test substance was used in the desiredconcentration, for competition. After an incubation time of 90 minutesat 4° C., the bound ligand was measured by scintillation (Halmos et al.,Proc. Natl. Acad. Sci. USA, 1996, 93, 2398).

Evaluation

The result obtained was the percentage proportion of bound ligand in thepresence of the competitor related to the specifically bound proportionof the control (see result for selected compounds in Table 3). EC₅₀values were calculated by nonlinear regression analysis of thecompetition plots.

TABLE 3 LHRH receptor-ligand binding assay test results, EC₅₀ and Kivalues for selected substances EC₅₀ Substance (M)  7 6.9 × 10⁻⁹ 48 8.0 ×10⁻⁹ 66 7.2 × 10⁻¹⁰ 67 6.9 × 10⁻⁹ 68 1.0 × 10⁻⁹ 75 5.9 × 10⁻¹⁰ 76 2.7 ×10⁻¹⁰

FIGS. 1-7 show the measured competition plots of the LHRHreceptor-ligand binding assay with [¹²⁵I][D-Trp6]-LH-RH and the selectedsubstances (7, 48, 66, 67, 68, 75 and 76)

II.1B LHRH Receptor-Ligand Binding Assay (Transfected LTK Cells)Materials:

¹²⁵I-Triptorelin [¹²⁵I-(D)-Trp6-GnRH] was purchased from Biotrend(Cologne, Germany).

The specific activity was in each case 2.13 Ci/mmol.

All other chemicals are purchased from commercial sources in the highestpurity available.

Cell Culture:

LTK cells (mouse fibroblasts: ATCC No. CCL-1.3) which have beentransfected with the rat LHRH receptor are cultivated in DMEM medium(Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml),streptomycin (0.1 mg/ml) and glutamine (0.01 mol/l) and 10% fetal calfserum (FCS; Invitrogen Life Technologies, Germany) on plastic tissueculture plates (Nunc, Germany, 245×245-20 mm).

Testing:

80% confluent cell culture plates are washed twice with 50 ml ofphosphate-buffered saline (PBS) and then detached with 0.01 M EDTAsolution. The cells are pelleted by centrifugation at 200·g for 5 min ina laboratory centrifuge (Kendro, Germany). The cell pellet isresuspended in 3 ml of binding medium (DMEM; 10 mM Hepes; 0.5% BSA; 0.1%NaN_(1; 1) g/l bacitracin (add fresh, stock 100×); 0.1 g/l SBTI (addfresh, stock 1000×) and the cell count is determined by Trypan bluestaining in a Neubauer counting chamber. The cell suspension is adjustedwith binding medium to a concentration of 5×10⁵ cells/0.05 ml.

Binding studies for competition plots are carried out as duplicates. Thetest substances are employed as 10 mM DMSO solutions. They are dilutedto 4 times the final concentration employed with binding medium. 25 μlof the substance dilution are mixed with 25 μl of tracer solution(¹²⁵I-triptorelin or ¹²⁵I-cetrorelix). The tracer concentration isadjusted to approx. 50 000 cpm (measured in a Cobra II, γ counter. PELiefe Science, Germany) in the final reaction volume of 100 μl.

200 μl of silicone/liquid paraffin mixture (84%:16%) are introduced into650 μl conical tubes (Roth. Germany). 50 μl of the cell suspension arepipetted thereon, followed by 50 μl of the test substance/tracermixture. The tubes are capped and incubated with vertical rotation in anincubator at 37° C. for 60 min. After incubation, the samples arecentrifuged in a centrifuge (Kendro, Germany) at 900 rpm andsubsequently shock-frozen in liquid N₂. The tip with the cell pellet iscut off and transferred into prepared counting vials (Roth, Germany).The remainder of the conical tube with the remaining supernatant islikewise transferred into a counting vial. The measurement takes placein a γ counter for 1 min/sample.

Evaluation of the samples takes place after calculation of the specificbinding compared with untreated cells, after subtraction of thenonspecific binding (excess of unlabeled ligand, 1 μM) by means ofGraphPad Prism or alternatively by means of OMMM software.

TABLE 4 LHRH receptor-ligand binding assay test results, EC₅₀ values fora number of selected exemplary substances Binding to Example r-LHRHR No.EC₅₀ [μM] Autonom name 1 0.2609 4-Chlorobenzyl{1-[3-(carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl- propyl}carbamate2 0.2051 4-Chlorobenzyl{1-[3-(carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl-butyl}carbamate 30.0472 4-Chlorobenzyl{1-[3-(carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl-butyl}carbamate 40.0048 6,8-Dichloro-3-{2-[2-(2-fluorophenyl)acetylamino]-3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (1-carbamoyl-2-methylbutyl)amide 5 0.098356,8-Dichloro-3-{2-[2-(3-fluorophenyl)acetylamino]-3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (1-carbamoyl-2-methylbutyl)amide 6 0.1037 2-Chlorobenzyl{1-[3-(1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl-butyl}carbamate 70.0079 Benzyl{1-{6,8-dichloro-3-[2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate 80.0453 Benzyl 4-{3-benzyloxycarbonylamino-3-[3-(1-carbamoyl-2-methyl-butylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]propyl}phenyl carbonate 10 0.0075 Benzyl[1-[6,8-dichloro-3-(2-methyl-1-thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-hydroxyphenyl)propyl]carbamate 11 0.01725 Benzyl[1-[3-(1-carbamoyl-2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-phosphono-oxyphenyl)propyl]carbamate 12 0.0392 Benzyl[1-[6,8-dichloro-3-(2-methyl-1-thiocarbamoyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-(4-phosphonooxyphenyl)propyl]carbamate 13 0.00246,8-Dichloro-3-{2-[2-(2-fluorophenyl)acetylamino]-3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid(2-methyl-1-thiocarbamoylbutyl)amide 14 0.002056,8-Dichloro-3-[2-[2-(2-fluorophenyl)acetylamino]-4-(4-hydroxyphenyl)butyrylamino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (2-methyl-1-thiocarbamoylbutyl)amide 16 0.628056,8-Dichloro-3-{2-[3-(4-fluorophenyl)propionylamino]-3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid(1-carbamoyl-2-methylpropyl)amide 17 0.52525-[3-(1-Carbamoyl-2-methylpropylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-5-[3-(4-fluorophenyl)propionylamino]pentylammonium trifluoroacetate 22 0.024656,8-Dichloro-3-[2-[3-(2-fluorophenyl)propionylamino]-4-(4-hydroxyphenyl)butyrylamino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (1-carbamoyl-2-methylbutyl)amide 23 0.07296,8-Dichloro-3-{2-[3-(2-fluorophenyl)propionylamino]-3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid(1-carbamoyl-2-methylbutyl)amide 24 0.0135 Benzyl{1-[6,8-dichloro-3-(2-methyl-1-thiocarbamoyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-3-[4-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-ethoxy)phenyl]propyl}carbamate 25 0.0042 Benzyl{1-[8-chloro-6-fluoro-3-(2-methyl-1-thiocarbamoyl-butylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methylbutyl}carbamate

II.2 Inhibition of LHRH-Induced LH Secretion from Rat Pituitary Cells inVitro Materials

The LH concentration in cell culture supernatants was measured using therat luteinizing hormone (rLH) enzyme immunoassay (EIA) system ELISA (RPN2562) from Amersham Pharmacia Biotech. All other chemicals used werefrom commercial sources in the highest purity available.

Cell Culture

Juvenile male Wistar rats (Harlan Winkelmann, Germany) were sacrificedby decapitation, and the pituitaries were removed and taken up in Hanks'buffer (HBSS) with 0 3% BSA and 10 mM HEPES (pH 7.4). Pituitaries from20 rats were required to carry out one experiment. The cells of theanterior lobe of the pituitary were separated from the remaining tissueby incubation in Hanks' buffer with 10 mM HEPES (pH 7.4), 0.3% BSA, 1mg/ml hyaluronidase (type VIII), 1 mg/ml soybean trypsin inhibitor, 10μg/ml DNAsel and 1 mg/ml papain at 37° C. for 30 minutes A sterilePasteur pipette was used to disperse the cells, and they weresubsequently pelleted by centrifugation. The cells were seeded in adensity of 2.5×10⁵ cells/well of a collagen-coated 48-well plate (BectonDickinson) in DMEM medium (Invitrogen Life Technologies, Germany) with10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany), 10mill nonessential amino acids and 10 mill Pen/Strep(penicillin/streptomycin).

Assay

The medium was changed after incubation at 37° C., 5% CO₂ and 95%humidity for 48 h. The medium was replaced by LHRH-containing (10 nM)medium or medium with LHRH (10 nM) and test substance in theconcentration indicated (table). After a further incubation for 3 hours,the cell supernatant was harvested and frozen at −20° C. The LH contentwas determined by means of ELISA in triplicate determination inaccordance with the manufacturer's (Amersham Pharmacia Biotech)instructions.

In the following table, “% Inhibition” describes the quotient ofLHRH-stimulated LH secretion with (“LH (ng/ml)” and without the additionof the test substance. The values originate from different, independentexperiments.

TABLE 5 Inhibition of LHRH-stimulated LH secretion from rat pituitarycells by selected substances Substance Concentration LH (ng/ml) ± SD %Inhibition 4 3.3 × 10⁻⁸ M 79.3 ± 5.7 67% 4 3.3 × 10⁻⁹ M — — 7 3.3 × 10⁻⁸M  79.9 ± 15.0 83% 7 3.3 × 10⁻⁹ M 194.0 ± 13.2 43% 10 3.3 × 10⁻⁸ M 118.7± 11.6 39% 10 3.3 × 10⁻⁹ M 198.8 ± 4.2   0%

II.3 LH Concentration Suppression in the Plasma of Castrated RatsMaterials

The LH concentration in the plasma of castrated rats was measured usingthe rat luteinizing hormone (rLH) enzyme immunoassay (EIA) system ELISA(RPN 2562) from Amersham Pharmacia Biotech or of LH RIA-AH R002 rats;from Biocode-Hycel, Liege, Belgium. All other chemicals used were fromcommercial sources in the highest purity available.

Animals

10 days before the start of the test, male Sprague Dawley rats (HarlanWinkelmann, Germany) weighing 190-220 g were anesthetized with ether andcastrated and provided with a silicone catheter for permanent bloodsampling.

Assay

At the start of the test, before administration of the substance, bloodsamples were taken and the LH level determined. The substance was thenadministered orally in the desired concentration. The number of animalsused in each group was 8. At the stated times, further blood sampleswere taken. The blood was collected in heparinized sample tubes on ice,and the plasma was obtained by centrifugation at 3000 g for 10 minutes.The plasma samples were stored at −20° C. until the LH concentration wasmeasured by ELISA or RIA. The LH concentration was determined by anELISA or RIA in duplicate determination in accordance with themanufacturer's (Amersham Pharmacia Biotech; Biocode-Hycel) instructions.

Evaluation and Statistics

Since the rats showed large differences in the individual LHconcentrations, owing to the physiological pulsatile secretion of LH,the values before treatment with the substance have been indicated asaverages of the individual LH concentrations and correspond to the 100%value. All the other data points for each individual animal werecalculated as relative concentration compared with the LH concentrationbefore treatment.

TABLE 6 Relative LH concentration in rat plasma after treatment withsubstance 7 in a dosage of 100 mg/kg in Solutol HS15/1,2-propane-diol(3:1) Relative LH concentration (%) (averages ± SEM compared Time withthe concentration before (h) treatment) −4  97.4 ± 15.3 −2 110.8 ± 12.20  91.8 ± 19.1 +4 19.6 ± 8.9 +6 10.1 ± 3.2 +24  65.1 ± 13.9 +48 110.6 ±33.0 +72 268.4 ± 93.0

TABLE 7 Relative LH concentration in rat plasma after treatment withsubstance 68 in a dosage of 19 mg/kg in Solutol HS15/1,2-propane-diol(3:1) Relative LH concentration (%) (averages ± SEM compared Time withthe concentration before (h) treatment) −24 105.4 ± 12.7 0 95.0 ± 9.3 +417.4 ± 3.3 +6 16.0 ± 1.5 +8 12.9 ± 1.0 +12 16.0 ± 2.6 +24  65.7 ± 10.8+30 78.1 ± 7.7

III. Demonstration of the Antagonistic Effect of the Compounds of theInvention of the General Formulae (I, Ia and Ib) on Receptors of theNeurokinin Family (NK₁ and NK₂)

Receptor affinities (IC₅₀ values) of the compounds of the invention ofthe general formulae (I, Ia and Ib) were measured as described by E.Heuillet et al., J. Neurochem., 60: 868-876 (1993) and D. Aharony et al.Mol. Pharmacol, 44: 356-363 (1993) commercially by Cerep (Assay 826-1hon page 67 and Assay 826-2h on page 68 of the 2005 catalogue).

Assay Substance IC50 (M) Ki (M) nH NK1 (h) 68 1.4E−06 6.4E−07 2.0 NK2(h) 68 1.6E−06 8.5E−07 3.8 NK1 (h) 76 1.9E−06 8.4E−07 2.3 NK2 (h) 761.5E−06 8.1E−07 2.3

FIGS. 8-11 show competition plots measured in the NK1 and NK2receptor-ligand binding assays with [Sar⁹, Met(O₂)¹¹]-SP for NK1 and[Nle¹⁰]-NKA(4-10) for NK2, and the selected substances (68 and 76).

IV. Demonstration of the Saturation Solubility in Water for theCompounds of the Invention of the General Formulae (I, Ia and Ib)

The saturation solubility in water was determined in accordance with thefollowing description: to initiate dissolving of the substances and toimprove the wetting of the samples, a maximum of 1% DMSO was added. Thecontent was checked by using an HPLC UV method. The results aresummarized in Table 8 below.

TABLE 8 Water solubilities of selected compounds Saturation solubilityin Compound water Compound name number [μg/ml] Benzyl[1-[3-(1-carbamoyl-2-methyl- 11  39.9butylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]- 3-(4-phosphonooxyphenyl)propyl]-carbamate Benzyl {1-{6,8-dichloro-3-[2-methyl-1- 7 54.6thiocarbamoylbutylcarbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]- 2-methylbutyl}carbamate Benzyl[1-[3-(1-carbamoyl-2-methyl- 9 150.6butylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]- 2-(4-phosphonooxyphenyl)ethyl]-carbamate Benzyl [1-[3-(1-carbamoyl-2-methyl- Example 295 <0.05butylcarbamoyl)-6,8-dichloro-2,3,4,9- fromtetrahydro-1H-carbazol-3-ylcarbamoyl]- WO 03/0518372-methylbutyl]carbamate A2 Benzyl (1-{3-[carbamoylcyclohexyl- Example300 0.38 methyl)carbamoyl]-6,8-dichloro-2,3,4,9- fromtetrahydro-1H-carbazol-3-ylcarbamoyl}- WO 03/0518372-methylbutyl)carbamate A2 Benzyl [1-[3-(1-carbamoyl-2-methyl- Example303 0.35 butylcarbamoyl)-6,8-dichloro-2,3,4,9- fromtetrahydro-1H-carbazol-3-ylcarbamoyl]- WO 03/0518373-(4-hydroxyphenyl)propyl]carbamate A2

V. Demonstration of the Metabolic Stability of the Compounds of theGeneral Formulae (I, Ia and Ib)

The metabolic stability in relation to liver microsomes (species human,rat) was determined in accordance with the following description: thesubstances were incubated at a test concentration of 1 or 10 μM with ratliver microsomes or human liver microsomes at 37° C. for 45 minutes withaddition of NADPH. An HPLC MS/MS method was subsequently used toquantify the unmetabolized amount of starting compound relative to 100%.The results are summarized in Table 9 below.

TABLE 9 Metabolic stability of selected compounds in relation to livermicrosomes of various species Metabolic Metabolic stability stability(rat) (human) Compound [1 h, % [1 h, % Compound name number recovery]recovery] Benzyl {(S)-1-[(R)-6,8-dichloro-3-  7 78% 65%((S)-2-methyl-1-thiocarbamoylbutyl- carbamoyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl]-2-methyl- butyl}carbamate (1 μM) Benzyl[(S)-1-[(R)-3-((S)-carbamoyl- 11 n.d. 77% 2-methylbutylcarbamoyl)-6,8-dichloro-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-3-(4-phosphonooxyphenyl)- propyl]carbamate (1 μM)(R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2- 68 80% 75%fluorophenyl)acetylamino]-3-methyl- pentanoylamino}-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S)- 2-methyl-1-thiocarbamoylbutyl)amide(10 μM) (R)-3-{(S)-2-[2-(2-Fluorophenyl)- 76 69% 84%acetylamino]-3-methylpentanoyl- amino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-methyl-1-thiocarbamoyl-butyl)amide (10 μM) Benzyl {(S)-1-[(R)-3-((S)-1-carbamoyl- Example 295from  0%  0% 2-methylbutylcarbamoyl)-6,8- WO 03/051837 A2dichloro-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-2-methyl-butyl]carbamate (1 μM) Benzyl {(S)-1-[(R)-3-((S)-1-carbamoyl- Example294 from  5%  0% 2-methylbutylcarbamoyl)-8- WO 03/051837 A2methoxy-2,3,4,9-tetrahydro-1H- carbazol-3-ylcarbamoyl]-2-methyl-butyl]carbamate (1 μM)

1-29. (canceled)
 30. A method for the treatment or prophylaxis of apathological condition mediated by a G-protein coupled receptor or of apathological condition which can be treated by modulation of a G-proteincoupled receptor, comprising administering an effective amount of acompound tetrahydrocarbazole compound of the formula (1)

in which: X₁ is S or O, X₂ and X₃ are independently of one another O orgeminally linked H₂, R1 and R2 are independently of one another selectedfrom the group consisting of —H, aryl, alkyl and arylalkyl radicalswhich are optionally substituted in the alkyl and/or aryl group by up to3 substituents independently selected from the group consisting of -Hal,—CN and —O-alkyl, where R1 and R2 are in particular hydrogen, R3 is analkyl, arylalkyl or heteroarylalkyl radical, which are optionallysubstituted by up to 3 substituents independently selected from thegroup consisting of -Hal, —CN, —CO—O—R12, —CO—NR12R12′, —OH, —O—R13,—O—CO—R13, —O—SO₂—OR12, —O—SO₂—R12, —SO₂—SO—R12, —SO—R12,—O—PO(OR12)(OR12′), —O—PO(NR12R12′)₂, —O—CO—O—R13, —O—CO-NR12R12′,—O—CS—NR12R12′, —S—R12, —NR12R12′, —NH—CO—R13, —NH—SO_—R12,—NH—CO—O—R13, —NH—CO—NHR12, —NH—C(NH)—NH₂, R4, R5, R6 and R7 areselected independently of one another from the group consisting of H,-Hal, —CN, —CONH₂, —COOH, —CF₃, —O-alkyl, —OCF₃, —NO₂—, and alkyl,arylalkyl and heteroarylalkyl radicals; R9 is a hydrogen atom, an alkyl,an aryl, a heteroaryl, an arylalkyl or a heteroarylalkyl radical; R10 isa hydrogen atom, or the radical —R11, —CO—R11, —CO—OR11, —CO—NHR11,—C(NH)—NHR11, —SO —R11, or —SO—)—NHR11; R11 is an alkyl, an aryl, aheteroaryl, an arylalkyl or a heteroarylalkyl radical, which areoptionally substituted by one or more substituents independentlyselected from the group consisting of -Hal, —CN, -alkyl, —CF₃, —OCF₃,—OH, —O-alkyl, and —O—(CH₂ CH₂—O)_(n)—CH₃; R8 is —C₁-C₆alkyl-aryl or—C₁-C₆-alkyl-heteroaryl, where the aryl or heteroaryl group issubstituted by one to three substituents independently selected from thegroup consisting of —O—(CH₂CH₂O)_(n)—CH₃, —O—CO—R12,—O—CO—(CH₂CH₂—O)_(n)—CH₃, —O—SO₂—OR12, —O—SO₂—R12, —O—PO(OR12)(OR12′),—O—PO(NR12R12′)₂—, —O—CO—OR13, —O—CO-NR12R12′, and —O—CS—NR12R12′, or,where, however, at least (i) X₁ is S, or (ii) R10 is not H, and R11 isan arylalkyl or heteroarylalkyl radical, which are substituted in thearyl or heteroaryl group by one or more substituents independentlyselected from the group consisting of Hal, —CN, -alkyl, —CF₃, —OCF₃,—OH, —O-alkyl, and —O—(CH₂CH₂—O_(n)—CH₃, R8 also assumes the meaningsindicated for R3; R12 and R12′ are independently of one another H, or analkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl radical; R13 isselected from an alkyl, arylalkyl, aryl, heteroarylalkyl, and heteroarylradical, or is the group —(CH₂CH₂—O)_(n)—CH₃, and n is an integer from 1to 10; and physiologically tolerated salts, derivatives or analogues ofthe compound of the formulae (1), where the salts are obtainable byneutralizing the bases with inorganic or organic acids or byneutralizing the acids with inorganic or organic bases, where thecompound of the formula (1) and its salts, derivatives or analogues maybe in the form of their racemates, in the form of the pure enantiomersand/or diastereomers or in the form of mixtures of these enantiomersand/or diastereomers, in the form of the tautomers, the solvates andhydrates thereof and the polymorphic forms thereof, to an individual inneed thereof.
 31. The method as claimed in claim 30, where the G-proteincoupled receptor is an LHRH receptor.
 32. The method as claimed in claim30, where the G-protein coupled receptor is a receptor of the neurokininfamily.
 33. The method as claimed in claim 31, where the compound asclaimed in claim 30 acts as an LHRH receptor antagonist.
 34. The methodas claimed in claim 42, where the compound as claimed in claim 30 actsas an antagonist of the NK₁ and/or of the NK₂ receptor.
 35. The methodas claimed in claim 31 for the treatment of a benign or malignantneoplastic disease, in male fertility control, in hormone therapy, inhormone replacement therapy, for the treatment and/or control of femalesub- or infertility, for controlled ovarian stimulation in in vitrofertilization, for female contraception, or for protection from sideeffects due to chemotherapy.
 36. The method as claimed in claim 31,where the pathological condition mediated by the LHRH receptor or thepathological condition which can be treated by modulation of the LHRHreceptor is selected from the group comprising: benign prostatehyperplasia (BPH), endometriosis, uterine fibroids, uterine myomas,endometrium hyperplasia, dysmenorrhoea, dysfunctional uterine bleeding(menorrhagia, metrorrhagia), pubertas praecox, hirsutism, polycysticovary syndrome, hormone-dependent neoplastic diseases, HIV infections orAIDS, neurological or neurodegenerative disorders, ARC (AIDS relatedcomplex), Kaposi sarcoma, tumors originating from the brain and/ornervous system and/or meninges, dementia and Alzheimer's disease. 37.The method as claimed in claim 36, where the hormone-dependentneoplastic disease is selected from the group consisting of: prostatecancer, breast cancer, uterine cancer, endometrial cancer, cervicalcancer, and ovarian cancer.
 38. The method as claimed in claim 32 forthe treatment and prevention of nausea and vomiting, for the treatmentof pain, inflammations and rheumatic and arthritic pathological states.39. The method as claimed in claim 32, where the G-protein coupledreceptor is an NK₁ and/or NK₂ receptor.